Topical therapy for the treatment of skin malignancies using nanoparticles of taxanes

ABSTRACT

Disclosed are methods useful for the topical therapeutic treatment of skin malignancies including skin cancers and cutaneous metastases using compositions containing nanoparticles of paclitaxel or other taxanes.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation under 35 U.S.C. § 111(a) ofInternational Patent Application No. PCT/US2018/022540, filed Mar. 15,2018, which claims the benefit of U.S. Provisional Application No.62/471,561, filed Mar. 15, 2017. The contents of the referencedapplications are incorporated into the present application by reference.

FIELD OF THE INVENTION

The present invention generally relates to the field of topicaltherapeutic treatment of skin malignancies including skin cancers andcutaneous metastases. In particular, the invention relates to the use oftopical compositions comprising taxane nanoparticles for treatment ofskin malignancies.

BACKGROUND OF THE INVENTION

Skin malignancies include skin cancers and cutaneous metastases. Skincancers form in the tissues of the skin. There are several types of skincancers which include melanoma (malignant melanoma), basal cellcarcinoma, squamous cell carcinoma, neuroendocrine carcinoma of theskin, Merkel cell tumors, dermatofibrosarcoma protruberans, and Kaposi'ssarcoma. The major types of skin cancers include melanoma, basal cellcarcinoma, and squamous cell carcinoma. Melanoma is a skin cancer thatforms in melanocytes (skin cells that make pigments). Basal cellcarcinoma forms in the lower part of the epidermis and squamous cellcarcinoma forms in squamous cells. Neuroendocrine carcinoma of the skinforms in neuroendocrine cells. The vast majority of skin cancers arebasal cell carcinomas and squamous cell carcinomas, and they generallydo not spread to other parts of the body (metastasize). Melanomas tendto spread to other parts of the body. Kaposi's sarcoma is a relativelyrare type of skin malignancy that afflicts the elderly or those with anabnormal immune system such as those with AIDS. Kaposi's sarcoma is alesion (tumor) of the skin characterized by soft purplish plaques andpapules that form nodules on the skin.

A cutaneous (skin) metastasis refers to a growth of cancer cells in theskin originating from an internal cancer or a skin cancer such asmelanoma. A cutaneous metastasis occurs when cancerous cells break awayfrom the primary cancer tumor and travel to the skin typically throughthe blood circulation or lymphatic system. Cutaneous metastases havebeen reported as manifestations of the following cancers: breast, lung,nasal sinus, larynx, oral cavity, colorectal, stomach, ovary, testis,bladder, prostate, cervical, vaginal, thyroid, endometrial, kidney,esophagus, pancreas, liver, melanoma and Kaposi's sarcoma (includingAIDS-related Kaposi's sarcoma). Cutaneous metastases are increasinglyprevalent and occur in approximately 10% of patients with metastaticcancer (Lookingbill et. al., Cutaneous metastases in patients withmetastatic carcinoma: A retrospective study of 4020 patients, J Am AcadDermatol 29:228-236, 1993). Women with skin metastases have thefollowing distribution in decreasing order of frequency of primarymalignancies: breast, ovary, oral cavity, lung, and large intestine. Inmen, the distribution is as follows: lung, large intestine, oral cavity,kidney, breast, esophagus, pancreas, stomach, and liver. (Alcaraz etal., Cutaneous Metastases from Internal Malignancies: AClinicopathologic and Immunohistochemical Review, Am J Dermatopathol34:347-393, 2012). With advances in cancer treatment, patients areliving longer and thus, are more likely to develop cutaneous metastases.

Generally, a cutaneous metastasis lesion is a firm, round or ovalmobile, non-painful nodule or nodules with intact overlying epidermis.Sometimes nodules develop ulceration and secondary infection. Othersigns of a skin metastasis can be the presence of plaques, papules, orred patches. Cutaneous metastases can cause pain, infection, bleedingand/or disfigurement, and can negatively impact the quality of life ofthe patient.

The incidence of cutaneous metastases in patients with breast carcinomawas recently reported as 23.9% (Lookingbill et. al.). Cutaneousmetastases from breast carcinoma are the most common metastases observedby dermatologists (De Giorgi et. al., Cutaneous manifestations of breastcarcinoma, Dermatol Therapy, 23:581-589, 2010). These cutaneousmetastases most commonly occur on the chest wall and abdomen, but mayalso occur at the extremities and on the head and neck region. Nodulesare the most common form of these cutaneous metastases. They range insize from 1 to 3 cm and are firm solitary or multiple lesions in thedermis or subcutaneous tissue.

Various treatments for skin cancer and cutaneous metastases areavailable including systemic therapy and skin-directed therapy. However,systemic therapy has limited efficacy with respect to treatment ofcutaneous metastases (Spratt et al., Efficacy of Skin-Directed Therapyfor Cutaneous Metastases from Advanced Cancer: A Meta-Analysis, J ClinOncol, 32:3144-3155, 2014).

Skin-directed therapy includes electrochemotherapy (ECT), photodynamictherapy (PDT), radiotherapy (RT), intralesional therapy (ILT), andtopical therapy. ECT, PDT, RT, and ILT all require administration by amedical practitioner or technician, whereas topical therapy can beadministered by the patient. Thus, topical therapy can be less costlythan other therapies and can also allow for greater patient compliancesince the therapy can be administered by the patient at home. However,topical therapy that included compositions of imiquimod or miltefosinefor the treatment of cutaneous metastases had low response rates andonly showed improved response rates when combined with otherskin-directed therapies (Spratt et. al.). In a meta-analysis of 47prospective studies of 4,313 cutaneous metastases, the objectiveresponse rate to the aforementioned therapies (including radiotherapy)was 60.2% (Spratt et al.). ECT demonstrated the best response rate(complete response rate 47.5%); however, ECT is an inpatient procedurerequiring general anesthesia and often results in notable pain anddermatologic toxicity (inflammation, hyperpigmentation, and ulceration)(Cabula et al., Electrochemotherapy in the Treatment of CutaneousMetastases from Breast Cancer: A Multicenter Cohort Analysis, Ann SurgOncol (2015) 22:S442-S450). The less invasive alternatives, such asintralesional therapy and topical therapy demonstrate reduced efficacyin comparison to ECT. When effective reduction of cutaneous metastasescannot be achieved, as is often the case, healthcare providers must fallback on palliative wound care remedies (Fernandez-Anton Martinez, etal., Metástasis cutáneas de origen visceral, Actas Dermosifiliogr. 2013;104(10):841-853). Thus, the availability of topical therapeuticcompositions that are efficacious in treating cutaneous metastaseswithout the need to combine the therapy with other skin-directedtherapies would be beneficial. There is therefore a significant unmetneed for an effective, less invasive alternative therapy for cutaneousmetastases in patients already struggling with significant morbidityfrom the symptoms of and treatments for advanced primary cancer.

Delivery of therapeutic drugs into viable epidermis and dermis of theskin can be a challenge due to the barrier properties of the stratumcorneum, the outermost layer of the epidermis. The delivery of poorlywater soluble drugs into the skin can be even more of a challenge. Skinpenetration enhancers have been employed in topical drug formulations toincrease the penetration of drugs into the skin and have had somesuccess. However, some penetration enhancers such as solvents andsurfactants can be irritating to the skin. Volatile silicone fluids havebeen employed in topical formulations to increase the penetration ofdrugs into the skin; however, high concentrations of volatile siliconefluids, i.e., 25% and greater, and/or combinations of volatile siliconefluids with other potential skin irritating compounds such as alcohols,e.g., C₁ to C₄ aliphatic alcohols, surfactants, other penetrationenhancers, and other volatile solvents have been needed to produce thepenetration enhancement effect. Additionally, some penetration enhancerswill cause the drug to penetrate transdermally and be systemicallyabsorbed, which is not desirable when only treating a condition of theskin (e.g., epidermis and/or dermis). Other topical delivery systemshave been employed where the drug is chemically modified withsurfactants and other substances, but these materials can also beirritating to the skin.

Taxanes, including paclitaxel and docetaxel, have been used for thetreatment of cancer for many years. These compounds are typicallycharacterized as being poorly water soluble. The cancer treatmentformulation initially developed for intravenous (IV) infusion injection,TAXOL® (BMS), is paclitaxel dissolved in a 50:50 v/v mixture ofpolyethoxylated castor oil (CREMOPHOR® EL) and dehydrated ethanol.However, the systemic use of this formulation results in significantclinical toxicity (Rowinsky et al. 1993). Substantial effort has beendevoted to the development of CREMOPHOR EL-free formulations ofpaclitaxel (Ma and Mumper, 2013). One such formulation is disclosed inU.S. Pat. No. 8,221,779, herein incorporated by reference, whichdiscloses injectable aqueous compositions of antimitotic drugmicroparticles, including paclitaxel, useful for the treatment ofcancers by intraperitoneal and intravenous (IV) injection of thecompositions.

Topical treatment of skin cancers currently includes topicalformulations of 5-fluorouracil (5-FU), imiquimod, and ingenol mebutate.However, the use of these formulations can cause local skin irritationsuch as burning, redness, dryness, pain, swelling, itching, tenderness,and ulceration at the site of application.

Currently, there are no FDA approved topical taxane formulations for thetreatment of skin cancer or cutaneous metastases in the U.S. Previoustopical therapy treatments of cutaneous metastases using compositionscontaining other active ingredients may have been ineffective in part,because of the inability of the composition to penetrate into the skinto the affected tissue.

SUMMARY OF THE INVENTION

The present invention provides solutions to the aforementionedlimitations and deficiencies in the art relating to the treatment ofskin malignancies including skin cancers and cutaneous metastases.Disclosed is a topical therapy that utilizes a topical composition withenhanced dermal penetration for the delivery of taxane nanoparticles toskin malignancies including skin cancers and cutaneous metastasesproviding effective treatment with low to negligible local skinirritation. In certain instances, the treatment methods of the presentinvention can be used without the need to combine them with other knownskin-directed therapies such as those discussed above.

In one aspect of the invention, disclosed is a method of treating a skinmalignancy in a subject in need of treatment, the method comprisingtopically administering (topically applying) to an affected area of thesubject a composition comprising a plurality of taxane nanoparticles.The “affected area” of a skin malignancy can include at least a portionof the skin where the skin malignancy lesion is visibly present on theoutermost surface of the skin or directly underneath the surface of theskin (epithelial/dermal covering), and can include areas of the skin inthe proximity of the skin malignancy likely to contain visiblyundetectable preclinical lesions. In some embodiments, the taxanenanoparticles are suspended within the composition. In otherembodiments, the taxane nanoparticles have a mean particle size (number)from 0.1 microns to 1.5 microns. In various embodiments, the taxanenanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, orcabazitaxel nanoparticles, or any combination of such nanoparticles. Insome embodiments, the taxane nanoparticles are paclitaxel nanoparticles.In some embodiments, the paclitaxel nanoparticles have a specificsurface area (SSA) of at least 18 m²/g, or from 18 m²/g to 40 m²/g. Theconcentration of the taxane nanoparticles in the compositions is at aconcentration effective to provide a therapeutic improvement in the skinmalignancy, which can be a skin cancer or a cutaneous metastasis. Insome embodiments, the effective concentration of the taxanenanoparticles or paclitaxel nanoparticles is about 0.15 to about 2% w/w,or 0.1 to 5% w/w. In some embodiments, the composition is anhydrous. Insome embodiments, the composition is a hydrophobic composition and cancomprise a hydrophobic carrier. In still other embodiments, thehydrophobic carrier is non-volatile and/or is non-polar. In variousembodiments, the hydrophobic carrier comprises a hydrocarbon which canbe petrolatum, mineral oil, or paraffin wax, or mixtures thereof. Insome embodiments, the mineral oil is heavy mineral oil. In someembodiments, the hydrophobic carrier is greater than 50% w/w of thecomposition. The hydrophobic composition can further comprise one ormore volatile silicone fluids. In some embodiments, the volatilesilicone fluid is at a concentration of 5 to 24% w/w of the compositionand can be cyclomethicone. In some embodiments, the cyclomethicone iscyclopentasiloxane. In various embodiments, the composition is asemi-solid composition and can be an ointment. In various embodiments,the composition does not contain volatile C₁-C₄ aliphatic alcohols orC₁-C₅ aliphatic alcohols, and/or does not contain additional penetrationenhancers, and/or does not contain additional volatile solvents, and/ordoes not contain surfactants, and/or does not contain a protein oralbumin. In some embodiments, the skin malignancy is a skin cancer. Insome embodiments, the skin cancer is melanoma, basal cell carcinoma,squamous cell carcinoma, and/or Kaposi's sarcoma. In some embodiments,the skin malignancy is a cutaneous metastasis. In some embodiments, thecutaneous metastasis is from lung cancer, breast cancer, colon cancer,oral cancer, ovarian cancer, kidney cancer, esophageal cancer, stomachcancer, and/or liver cancer; and/or Kaposi's sarcoma (includingAIDS-related Kaposi's sarcoma). In still other embodiments, thetherapeutic method does not include additional skin-directed therapies.

In another aspect of the invention, there is disclosed a method ofenhancing penetration of taxane nanoparticles into a skin malignancy ofa subject, the method comprising topically applying to the affected areaa hydrophobic composition comprising a continuous hydrophobic carrier,one or more volatile silicone fluids, and a plurality of taxanenanoparticles. In some embodiments, the taxane nanoparticles aresuspended within the composition. In other embodiments, the taxanenanoparticles have a mean particle size (number) from 0.1 microns to 1.5microns. In various embodiments, the taxane nanoparticles are paclitaxelnanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles, orany combination of such nanoparticles. In some embodiments, the taxanenanoparticles are paclitaxel nanoparticles. In some embodiments, thepaclitaxel nanoparticles have a specific surface area (SSA) of at least18 m²/g, or from 18 m²/g to 40 m²/g. In some embodiments, theconcentration of the taxane nanoparticles or paclitaxel nanoparticles isabout 0.15 to about 2% w/w, or 0.1 to 5% w/w. In some embodiments, thecomposition is anhydrous. In some embodiments, the composition is ahydrophobic composition and can comprise a hydrophobic carrier. In stillother embodiments, the hydrophobic carrier is non-volatile and/or isnon-polar. In various embodiments, the hydrophobic carrier comprises ahydrocarbon which can be petrolatum, mineral oil, or paraffin wax, ormixtures thereof. In some embodiments, the mineral oil is heavy mineraloil. In some embodiments, the hydrophobic carrier is greater than 50%w/w of the composition. The hydrophobic composition can further compriseone or more volatile silicone fluids. In some embodiments, the volatilesilicone fluid is at a concentration of 5 to 24% w/w of the compositionand can be cyclomethicone. In some embodiments, the cyclomethicone iscyclopentasiloxane. In various embodiments, the composition is asemi-solid composition and can be an ointment and can have a viscosityof 25,000 cps to 500,000 cps as measured with a Brookfield RV viscometeron a helipath stand with the helipath on, with a T-E spindle at 10 RPMat room temperature for 45 seconds. In various embodiments, thecomposition does not contain volatile C₁-C₄ aliphatic alcohols or C₁-C₅aliphatic alcohols, and/or does not contain additional penetrationenhancers, and/or does not contain additional volatile solvents, and/ordoes not contain surfactants, and/or does not contain a protein oralbumin. In some embodiments, the skin malignancy is a skin cancer. Insome embodiments, the skin cancer is melanoma, basal cell carcinoma,squamous cell carcinoma, and/or Kaposi's sarcoma. In some embodiments,the skin malignancy is a cutaneous metastasis. In some embodiments, thecutaneous metastasis is from lung cancer, breast cancer, colon cancer,oral cancer, ovarian cancer, kidney cancer, esophageal cancer, stomachcancer, and/or liver cancer; and/or Kaposi's sarcoma (includingAIDS-related Kaposi's sarcoma). In some embodiments, the penetration ofthe taxane nanoparticles from the hydrophobic composition into the skinmalignancy is greater than the penetration of taxane nanoparticles intothe skin malignancy from topically applying a hydrophobic compositionthat comprises a plurality of taxane nanoparticles and that does notcontain one or more volatile silicone fluids.

In another aspect of the inventions, disclosed is a method of enhancingpenetration of taxane nanoparticles into a skin malignancy of a subject,the method comprising topically applying a hydrophobic compositioncomprising a plurality of taxane nanoparticles to the affected area,wherein the penetration of the taxane nanoparticles from the hydrophobiccomposition into the skin malignancy is greater than the penetration oftaxane nanoparticles into the skin malignancy from topically applying anaqueous based composition comprising a plurality of taxanenanoparticles. In some embodiments, the taxane nanoparticles have a meanparticle size (number) from 0.1 microns to 1.5 microns. In someembodiments, taxane nanoparticles are paclitaxel nanoparticles,docetaxel nanoparticles, or cabazitaxel nanoparticles, or anycombination of such nanoparticles. In some embodiments, hydrophobiccomposition further comprises a hydrophobic carrier.

As disclosed in international publication WO 2017/049083 (applicationPCT/US2016/052133) herein incorporated by reference, it was found thathydrophobic compositions of the present invention having a volatilesilicone fluid at concentrations less than 25% w/w in combination withan anhydrous hydrophobic carrier exhibited greater skin penetration(i.e., penetration into the epidermal and dermal portions of the skin)of taxane nanoparticles as compared to the skin penetration of taxanenanoparticles from the hydrophobic carrier alone. Surprisingly, it wasalso discovered that, other than the low amounts of volatile siliconefluid (less than 25 w/w %), the addition of other skin penetrationenhancers to the hydrophobic compositions had little or no effect on theskin penetration of the compositions. Therefore, the compositions of thepresent invention can be free of (do not have to include) theseadditional skin penetration enhancers (e.g., surfactants, volatilesolvents, alcohols, C₁-C₄ aliphatic alcohols or C₁-C₅ aliphaticalcohols), which can be helpful in reducing skin irritation when thecompositions of the present invention are applied to the skin. Even moresurprising is that the enhanced penetration was accomplished with lowconcentrations of cyclomethicone, i.e., less than 25% w/w. Additionally,the taxane nanoparticles are not transdermally delivered with thesecompositions initially after administration, which is a favorablefeature because transdermal delivery (systemic absorption) is notdesired when treating the skin (epidermis and dermis). Furthermore, theskin penetration (i.e., penetration into the dermal or epidermalportions of the skin) of taxane nanoparticles from the compositions ofthe present invention was far superior to the skin penetration of taxanenanoparticles from aqueous based compositions, even though the aqueousbased compositions contained a skin penetration enhancer. Additionally,it was found that the taxane nanoparticles were stable and did notexhibit crystal grow over time in the hydrophobic compositions of thepresent invention.

Hydrophobic compositions which comprise nanoparticles of a taxane, e.g.,paclitaxel, and a volatile silicone fluid in combination with ahydrophobic carrier, are especially suitable for the topical treatmentof skin malignancies including skin cancers and cutaneous metastasesbecause of the aforementioned enhanced penetration properties of thesecompositions into the epidermis and dermis portions of the skin. Thehydrophobic carrier can be the continuous phase of the composition withthe nanoparticles suspended therein.

Also, disclosed in the context of the present invention are thefollowing embodiments 1 to 71:

Embodiment 1 is a method of treating a skin malignancy in a subject inneed of treatment, the method comprising topically administering to anaffected area of the subject a composition comprising a plurality oftaxane nanoparticles.

Embodiment 2 is the method of embodiment 1, wherein the taxanenanoparticles are suspended within the composition.

Embodiment 3 is the method of any one of embodiments 1 to 2, wherein thetaxane nanoparticles have a mean particle size (number) from 0.1 micronsto 1.5 microns.

Embodiment 4 is the method of any one of embodiments 1 to 3, wherein thetaxane nanoparticles are paclitaxel nanoparticles, docetaxelnanoparticles, or cabazitaxel nanoparticles.

Embodiment 5 is the method of embodiment 4, wherein the taxanenanoparticles are paclitaxel nanoparticles.

Embodiment 6 is the method of embodiment 5, wherein the paclitaxelnanoparticles have a specific surface area (SSA) of at least 18 m²/g.

Embodiment 7 is the method of embodiment 6, wherein the paclitaxelnanoparticles have a specific surface area (SSA) of 18 m²/g to 40 m²/g.

Embodiment 8 is the method of any of embodiments 1 to 7, wherein theconcentration of the taxane nanoparticles is at a concentrationeffective to provide a therapeutic improvement in the skin malignancy.

Embodiment 9 is the method of embodiment 8, wherein the concentration ofthe paclitaxel nanoparticles is about 0.15 to about 2% w/w, or 0.1 to 5%w/w.

Embodiment 10 is the method of any one of embodiments 1 to 9, whereinthe composition is anhydrous.

Embodiment 11 is the method of any one of embodiments 1 to 10, whereinthe composition is a hydrophobic composition.

Embodiment 12 is the method of embodiment 11, wherein the hydrophobiccomposition comprises a hydrophobic carrier.

Embodiment 13 is the method of embodiment 12, wherein the hydrophobiccarrier is non-volatile.

Embodiment 14 is the method of any one of embodiments 12 to 13, whereinthe hydrophobic carrier is non-polar.

Embodiment 15 is the method of any one of embodiments 12 to 14, whereinthe hydrophobic carrier comprises a hydrocarbon.

Embodiment 16 is the method of embodiment 15, wherein the hydrocarbon ispetrolatum, mineral oil, or paraffin wax, or mixtures thereof.

Embodiment 17 is the method of embodiment 16, wherein the mineral oil isheavy mineral oil.

Embodiment 18 is the method of any one of embodiments 12 to 17, whereinthe hydrophobic carrier is greater than 50% w/w of the composition.

Embodiment 19 is the method of any one of embodiments 12 to 18, whereinthe hydrophobic composition comprises one or more volatile siliconefluids.

Embodiment 20 is the method of embodiment 19, wherein the concentrationof the one or more volatile silicone fluids is from 5 to 24% w/w of thecomposition.

Embodiment 21 is the method of embodiment 20, wherein the volatilesilicone fluid is cyclomethicone.

Embodiment 22 is the method of embodiment 21, wherein the cyclomethiconeis cyclopentasiloxane.

Embodiment 23 is the method of any one of embodiments 1 to 22, whereinthe composition is a semi-solid composition.

Embodiment 24 is the method of embodiment 23, wherein the semi-solidcomposition is an ointment.

Embodiment 25 is the method of any one of embodiments 1 to 24, whereinthe composition does not contain volatile C₁-C₄ aliphatic alcohols.

Embodiment 26 is the method of any one of embodiments 1 to 25, whereinthe composition does not contain additional penetration enhancers.

Embodiment 27 is the method of any one of embodiments 1 to 26, whereinthe composition does not contain additional volatile solvents.

Embodiment 28 is the method of any one of embodiments 1 to 27, whereinthe composition does not contain surfactants.

Embodiment 29 is the method of any one of embodiments 1 to 28, whereinthe composition does not contain a protein or albumin.

Embodiment 30 is the method of any one of embodiments 1 to 29, whereinthe skin malignancy is a skin cancer.

Embodiment 31 is the method of embodiment 30, wherein the skin cancer ismelanoma, basal cell carcinoma, squamous cell carcinoma, or Kaposi'ssarcoma.

Embodiment 32 is the method of any one of embodiments 1 to 29, whereinthe skin malignancy is a cutaneous metastasis.

Embodiment 33 is the method of embodiment 32, wherein the cutaneousmetastasis is from lung cancer, breast cancer, colon cancer, oralcancer, ovarian cancer, kidney cancer, esophageal cancer, stomachcancer, liver cancer, and/or Kaposi's sarcoma.

Embodiment 34 is the method of any one of embodiments 1 to 33, whereinthe method does not include additional skin-directed therapies.

Embodiment 35 is a method of enhancing penetration of taxanenanoparticles into a skin malignancy of a subject, the method comprisingtopically applying to the affected area a hydrophobic compositioncomprising a continuous hydrophobic carrier, one or more volatilesilicone fluids, and a plurality of taxane nanoparticles.Embodiment 36 is the method of embodiment 35, wherein the taxanenanoparticles are suspended within the hydrophobic composition.Embodiment 37 is the method of any one of embodiments 35 to 36, whereinthe taxane nanoparticles have a mean particle size (number) from 0.1microns to 1.5 microns.Embodiment 38 is the method of any one of embodiments 35 to 37, whereinthe taxane nanoparticles are paclitaxel nanoparticles, docetaxelnanoparticles, or cabazitaxel nanoparticles.Embodiment 39 is the method of embodiment 38, wherein the taxanenanoparticles are paclitaxel nanoparticles.Embodiment 40 is the method of embodiment 39, wherein the paclitaxelnanoparticles have a specific surface area (SSA) of at least 18 m²/g.Embodiment 41 is the method of embodiment 40, wherein the paclitaxelnanoparticles have a specific surface area (SSA) of 18 m²/g to 40 m²/g.Embodiment 42 is the method of any one of embodiments 39 to 42 whereinthe concentration of the paclitaxel nanoparticles is about 0.15 to about2% w/w, or 0.1 to 5% w/w.Embodiment 43 is the method of any one of embodiments 35 to 42, whereinthe composition is anhydrous.Embodiment 44 is the method of any one of embodiments 35 to 43, whereinthe hydrophobic carrier is non-volatile.Embodiment 45 is the method of any one of embodiments 35 to 44, whereinthe hydrophobic carrier is non-polar.Embodiment 46 is the method of any one of embodiments 35 to 45, whereinthe hydrophobic carrier comprises a hydrocarbon.Embodiment 47 is the method of embodiment 46, wherein the hydrocarbon ispetrolatum, mineral oil, or paraffin wax, or mixtures thereof.Embodiment 48 is the method of embodiment 47, wherein the mineral oil isheavy mineral oil.Embodiment 49 is the method of any one of embodiments 35 to 48, whereinthe hydrophobic carrier is greater than 50% w/w of the composition.Embodiment 50 is the method of any one of embodiments 35 to 49, whereinthe concentration of the one or more volatile silicone fluids is from 5to 24% w/w of the composition.Embodiment 51 is the method of embodiment 50, wherein the volatilesilicone fluid is cyclomethicone.Embodiment 52 is the method of embodiment 51, wherein the cyclomethiconeis cyclopentasiloxane.Embodiment 53 is the method of any one of embodiments 35 to 52, whereinthe composition is a semi-solid composition.Embodiment 54 is the method of embodiment 53, wherein the semi-solidcomposition is an ointment.Embodiment 55 is the method of any one of embodiments 53 to 54, whereinthe viscosity of the composition is 25,000 cps to 500,000 cps asmeasured with a Brookfield RV viscometer on a helipath stand with thehelipath on, with a T-E spindle at 10 RPM at room temperature for 45seconds.Embodiment 56 is the method of any one of embodiments 35 to 55, whereinthe composition does not contain volatile C₁-C₄ aliphatic alcohols.Embodiment 57 is the method of any one of embodiments 35 to 56, whereinthe composition does not contain additional penetration enhancers.Embodiment 58 is the method of any one of embodiments 35 to 57, whereinthe composition does not contain additional volatile solvents.Embodiment 59 is the method of any one of embodiments 35 to 58, whereinthe composition does not contain surfactants.Embodiment 60 is the method of any one of embodiments 35 to 59, whereinthe composition does not contain a protein or albumin.Embodiment 61 is the method of any one of embodiments 35 to 60, whereinthe skin malignancy is a skin cancer.Embodiment 62 is the method of embodiment 61, wherein the skin cancer isselected from melanoma, basal cell carcinoma, and squamous cellcarcinoma.Embodiment 63 is the method of any one of embodiments 35 to 60, whereinthe skin malignancy is a cutaneous metastasis.Embodiment 64 is the method of embodiment 63, wherein the cutaneousmetastasis is from lung cancer, breast cancer, colon cancer, oralcancer, ovarian cancer, kidney cancer, esophageal cancer, stomachcancer, liver cancer, and/or Kaposi's sarcoma.Embodiment 65 is the method of any one of embodiments 35 to 64, whereinthe penetration of the taxane nanoparticles from the hydrophobiccomposition into the skin malignancy is greater than the penetration oftaxane nanoparticles into the skin malignancy from topically applying ahydrophobic composition that comprises a plurality of taxanenanoparticles and that does not contain one or more volatile siliconefluids.Embodiment 66 is a method of enhancing penetration of taxanenanoparticles into a skin malignancy of a subject, the method comprisingtopically applying a hydrophobic composition comprising a plurality oftaxane nanoparticles to the affected area, wherein the penetration ofthe taxane nanoparticles from the hydrophobic composition into the skinmalignancy is greater than the penetration of taxane nanoparticles intothe skin malignancy from topically applying an aqueous based compositioncomprising a plurality of taxane nanoparticles.Embodiment 67 is the method of embodiment 66, wherein the taxanenanoparticles have a mean particle size (number) from 0.1 microns to 1.5microns.Embodiment 68 is the method of any one of embodiments 66 to 67, whereinthe taxane nanoparticles are paclitaxel nanoparticles, docetaxelnanoparticles, or cabazitaxel nanoparticles.Embodiment 69 is the method of any one of embodiments 66 to 68, whereinthe hydrophobic composition further comprises a hydrophobic carrier.Embodiment 70 is the method of any one of embodiments 66 to 69, whereinthe skin malignancy is a skin cancer or a cutaneous metastasis.Embodiment 71 is the method of any one of embodiments 66 to 70, whereinthe hydrophobic composition comprises a continuous hydrophobic phasehaving the plurality of taxane nanoparticles suspended therein.

The terms “nanoparticle”, “nanoparticles”, and “nanoparticulate”, asused herein with regard to taxane particles, represent the mean particlesize (based on the number-weighted differential distribution, designatedas “number”) of the taxane particles which is from 0.01 microns to 1.5microns (10 nm to 1500 nm) or preferably from 0.1 microns to 1.5 microns(100 nm to 1500 nm).

The term “water soluble,” as used herein, describes compounds that havea solubility in water of greater than 10 mg/mL or greater at roomtemperature.

The term “poorly water soluble,” as used herein, describes compoundsthat have a solubility in water of less than or equal to 10 mg/mL atroom temperature.

The term “hydrophobic,” as used herein, describes compounds,compositions, or carriers that have a solubility in water of less thanor equal to 10 mg/mL at room temperature.

The term “volatile,” as used herein, describes compounds, compositions,or carriers that have a vapor pressure greater than or equal to 10 Pa atroom temperature.

The term “non-volatile,” as used herein, describes compounds,compositions, or carriers that have a vapor pressure less than 10 Pa atroom temperature.

The term “anhydrous,” as used herein with regard to the compositions orcarriers of the invention, means that less than 3% w/w, preferably lessthan 2% w/w, more preferably less than 1% w/w, or most preferably 0% w/wof water is present in the compositions or carriers. This can accountfor small amounts of water being present (e.g., water inherentlycontained in any of the ingredients of the compositions or carriers,water contracted from the atmosphere, etc.).

The terms “skin” or “cutaneous” as used herein mean the epidermis and/orthe dermis.

The term “skin malignancy” as used herein includes skin cancers andcutaneous metastases.

The “affected area” of a skin malignancy can include at least a portionof the skin where the skin malignancy lesion (tumor) is visibly presenton the outermost surface of the skin or directly underneath the surfaceof the skin (epithelial/dermal covering), and can include areas of theskin in the proximity of the skin malignancy likely to contain visiblyundetectable preclinical lesions.

The terms “cutaneous metastasis”, “cutaneous metastases” (plural), “skinmetastasis”, “skin metastases” (plural), “cutaneous metastaticlesion(s)”, “skin metastatic lesion(s)”, “cutaneous metastasislesion(s)”, “skin metastasis lesion(s)”, “skin metastatic disease”, or“cutaneous metastatic disease” as used herein means the manifestation ofa malignancy in the skin as a secondary growth (tumor/lesion) arisingfrom the primary growth of a cancer tumor at another location of thebody. Spread from the primary tumor can be through the lymphatic orblood circulation systems, or by other means.

The terms “skin-directed therapy” or “skin-directed therapies” as usedherein means electrochemotherapy (ECT), photodynamic therapy (PDT),radiotherapy (RT), intralesional therapy (ILT), or topical therapy.

The terms “subject” or “patient” as used herein mean a vertebrateanimal. In some embodiments, the vertebrate animal can be a mammal. Insome embodiments, the mammal can be a primate, including a human.

The term “room temperature” (RT) as used herein, means 20-25° C.

The term “penetration enhancer” or “skin penetration enhancer” as usedherein, means a compound or a material or a substance that facilitatesdrug absorption into the skin (epidermis and dermis).

The term “surfactant” or “surface active agent” as used herein, means acompound or a material or a substance that exhibits the ability to lowerthe surface tension of water or to reduce the interfacial tensionbetween two immiscible substances.

Unless otherwise specified, the percent values expressed herein areweight by weight and are in relation to the weight of the totalcomposition.

The term “about” or “approximately” are defined as being close to asunderstood by one of ordinary skill in the art. In one non-limitingembodiment the terms are defined to be within 10%, preferably within 5%,more preferably within 1%, and most preferably within 0.5%.

For this application, a number value with one or more decimal places canbe rounded to the nearest whole number using standard roundingguidelines, i.e. round up if the number being rounded is 5, 6, 7, 8, or9; and round down if the number being rounded is 0, 1, 2, 3, or 4. Forexample, 3.7 can be rounded to 4.

The words “comprising” (and any form of comprising, such as “comprise”and “comprises”), “having” (and any form of having, such as “have” and“has”), “including” (and any form of including, such as “includes” and“include”) or “containing” (and any form of containing, such as“contains” and “contain”) are inclusive or open-ended and do not excludeadditional, unrecited elements or method steps.

The use of the word “a” or “an” when used in conjunction with the terms“comprising,” “having,” “including,” or “containing” (or any variationsof these words) may mean “one,” but it is also consistent with themeaning of “one or more,” “at least one,” and “one or more than one.”

The compositions and methods for their use can “comprise,” “consistessentially of,” or “consist of” any of the ingredients or stepsdisclosed throughout the specification. With respect to the phrase“consisting essentially of,” a basic and novel property of thecompositions of the present invention are their ability to topicallytreat skin malignancies. With respect to hydrophobic compositions of thepresent invention, a basic and novel property includes the ability to askin malignancy and the ability to have the nanoparticles moreeffectively penetrate into the epidermal and dermal layers of the skinwith limited to no penetration transdermally. This can be achievedwithout the use of C₁-C₄ aliphatic alcohols or C₁-C₅ aliphatic alcohols,surfactants, and additional skin penetration enhancers and additionalvolatile solvents other than a volatile silicone fluid(s) (e.g.,cyclomethicone or cyclopentasiloxane, or a combination thereof).

“Limited,” “reduced,” or “minimal” when modifying the phrase“penetration transdermally” means wherein less than 0.01 μg/cm² of thedrug nanoparticles penetrate through human cadaver skin when thecomposition is applied to the human cadaver skin as determined by an invitro Franz diffusion cell system.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method or composition of theinvention, and vice versa. Furthermore, compositions of the inventioncan be used to achieve methods of the invention.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating specific embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 graphically shows the concentration of paclitaxel (μg/cm2)delivered in vitro into the epidermis for formulas F1 through F7.

FIG. 2 graphically shows the concentration of paclitaxel (μg/cm2)delivered in vitro into the epidermis for formulas F6*(repeat analysis)and F8 through F13.

FIG. 3 graphically shows the concentration of paclitaxel (μg/cm2)delivered in vitro into the dermis for formulas F1 through F7.

FIG. 4 graphically shows the concentration of paclitaxel (μg/cm2)delivered in vitro into the dermis for formulas F6*(repeat analysis) andF8 through F13.

FIG. 5 is a photo of a skin metastatic lesion on the chest of a womanwith Stage 4 breast cancer at baseline (Day 1).

FIG. 6 is a photo of a skin metastatic lesion on the chest of a womanwith Stage 4 breast cancer at Day 8 after topical treatment.

FIG. 7 is a photo of a skin metastatic lesion on the chest of a womanwith Stage 4 breast cancer at Day 15 after topical treatment.

FIG. 8 is a photo of a skin metastatic lesion on the chest of a womanwith Stage 4 breast cancer at Day 29 after topical treatment.

DETAILED DESCRIPTION OF THE INVENTION

In some aspects, the invention relates to methods of treatment of skinmalignancies including skin cancers and cutaneous metastases in apatient by topically applying to the affected area (topical therapy) acomposition comprising a taxane(s). In some embodiments, the taxane ispaclitaxel. In other embodiments, the taxane is docetaxel orcabazitaxel. In further embodiments, a combination of taxanes can beused (e.g., paclitaxel and docetaxel, or paclitaxel and cabazitaxel, ordocetaxel and cabazitaxel, or paclitaxel, docetaxel, and cabazitaxel).In some embodiments, the composition comprises a carrier. In someembodiments, the carrier is anhydrous and/or hydrophobic. In otheraspects, the carrier is aqueous based. In some embodiments, thetaxane(s) is a plurality of nanoparticles of the taxane(s). In otherembodiments, the taxane(s) is solubilized. Suitable compositions for usein the methods of the invention are disclosed in international patentpublication WO 2017/049083 (application number PCT/US2016/052133),herein incorporated by reference. In a preferred embodiment, thecomposition is a hydrophobic composition comprising a continuoushydrophobic carrier, one or more volatile silicone fluids, and aplurality of taxane nanoparticles, wherein the taxane nanoparticles aresuspended within the composition and wherein the mean particle size(number) of the taxane nanoparticles is from 0.1 microns to 1.5 microns.In some embodiments, the concentration of the one or more volatilesilicone fluids is 5 to 24% w/w. In some embodiments, the compositiondoes not contain volatile C₁-C₄ aliphatic alcohols or C₁-C₅ aliphaticalcohols. In some embodiments, the concentration of the taxanenanoparticles is at a concentration effective to provide a therapeuticimprovement in the skin malignancy. In some embodiments, theconcentration of the taxane nanoparticles is at a concentration of about0.1 to about 2% w/w, or about 0.15 to about 2% w/w, or 0.1 to 5% w/w. Insome embodiments, the method does not include additional skin-directedtherapies, such as electrochemotherapy (ECT), photodynamic therapy(PDT), radiotherapy (RT), or intralesional therapy (ILT).

In some embodiments, the cutaneous metastasis is from one or more of theof the following cancers: breast, lung, nasal sinus, larynx, oralcavity, colorectal, stomach, ovary, testis, bladder, prostate, cervical,vaginal, thyroid, endometrial, kidney, esophagus, pancreas, liver,melanoma, and Kaposi's sarcoma (including AIDS-related Kaposi'ssarcoma). In some embodiments, the skin cancer is melanoma, basal cellcarcinoma, and/or squamous cell carcinoma.

I. Compositions

In one aspect of the invention, the compositions of the presentinvention are hydrophobic and comprise a continuous hydrophobic carrier,one or more volatile silicone fluids (such as cyclomethicone), and aplurality of taxane nanoparticles. The compositions can be suspensionsof a plurality of the taxane nanoparticles within a mixture of thehydrophobic carrier and the volatile silicone fluid. The taxanenanoparticles can be completely dispersed, or partially dispersed andpartially dissolved in the compositions. In various embodiments, thetaxane nanoparticles are not completely dissolved in the compositions.The hydrophobic compositions can be anhydrous. A hydrophobic compositionis a composition in which the total amount of the hydrophobicconstituents in the composition is greater than the total amount of thenon-hydrophobic constituents in the composition. The hydrophobic carriercan be the continuous phase of the hydrophobic compositions. Therefore,the compositions of the present invention can include at least twophases, a continuous hydrophobic carrier phase and a suspended taxanenanoparticle phase. The volatile silicone fluid can be solubilizedand/or dispersed within the continuous phase.

Surprisingly, the hydrophobic compositions of the invention that includevolatile silicone fluids at low concentrations, i.e., less than 25% w/w,in combination with a continuous, anhydrous hydrophobic carrier,exhibited greater skin penetration (i.e., penetration into the epidermaland/or dermal portions of the skin) of taxane nanoparticles as comparedto the skin penetration of taxane nanoparticles from the hydrophobiccarrier alone. In fact, and even more surprising, the addition of otherskin penetration enhancers had little or no effect on the skinpenetration of these compositions. Notably, however, the taxanenanoparticles did not penetrate through the skin (i.e., transdermalpenetration) or only a negligible amount penetrated transdermallythrough the skin, i.e. less than 0.01 μg/cm². Furthermore, the skinpenetration (i.e., epidermal or dermal penetration) of taxanenanoparticles from the anhydrous hydrophobic compositions was farsuperior to the skin penetration of taxane nanoparticles from aqueousbased compositions even though the aqueous based compositions containeda skin penetration enhancer. Additionally, and also surprisingly, thehydrophobic compositions of the invention that include less than 25% ofa volatile silicone fluid in combination with a hydrophobic carrier, donot need to contain alcohols, additional volatile solvents, additionalpenetration enhancers, or surfactants to provide enhanced skinpenetration, thereby allowing for a most cost-efficient and simplifiedcomposition that can have reduced skin irritancy when topically applied.If desired, however, such components can be included in the compositionsof the present invention. In some embodiments, the hydrophobiccompositions are free of/do not include or contain additionalpenetration enhancers. In some embodiments, the hydrophobic compositionsare free of/do not include or contain laurocapram. In some embodiments,the hydrophobic compositions are free of/do not include diethyleneglycol monoethyl ether (DGME). In some embodiments, the hydrophobiccompositions are free of/do not include isopropyl myristate. In otherembodiments, the hydrophobic compositions are free of/do not includealpha tocopherol. In other embodiments, the hydrophobic compositions arefree of/do not include or contain additional volatile solvents orcompounds. In some embodiments, the hydrophobic compositions are freeof/do not include or contain any alcohols or C₁-C₄ aliphatic alcohols.In some embodiments, the hydrophobic compositions are free of/do notinclude or contain alcohol or C₁-C₅ aliphatic alcohols. In otherembodiments, the hydrophobic compositions are free of/do not include orcontain surfactants. In other embodiments, the hydrophobic compositionsare free of/do not include polymers/copolymers (or biodegradablepolymers/copolymers). In other embodiments, the hydrophobic compositionsare free of/do not include poloxamers, styrene-isobutylene-styrene(SIBS), a polyanhydride copolymer, polycaprolactone, polyethyleneglycol, Poly (bis(P-carboxyphenoxy)propane-sebacic acid, and/or poly(D,L lactic-co-glycolic acid (PLGA). In various embodiments, the volatilesilicone fluid is a cyclomethicone. In other embodiments, thecyclomethicone is cyclopentasiloxane. In some embodiments, thehydrophobic compositions are semi-solid compositions. In otherembodiments the hydrophobic compositions are ointments. In someembodiments, the hydrophobic compositions are not sprays and are notsprayable.

In some embodiments, the hydrophobic compositions are semi-solidcompositions, including ointments, and have a viscosity of from 12,500cps to 247,500 cps, or from 25,000 cps to 150,000 cps as measured atroom temperature by a Brookfield RV viscometer using a small sampleadapter with a SC4-14 spindle and a 6R chamber at 5 rpm with anequilibration time of 2 minutes. An alternative method for performingviscosity measurements of the hydrophobic, semi-solid compositions isusing a Brookfield RV viscometer on a helipath stand with the helipathon, with a T-E spindle at 10 RPM at room temperature for 45 seconds. Insome embodiments, the hydrophobic compositions are semi-solidcompositions, including ointments, and have a viscosity of from 25,000cps to 500,000 cps, or from 25,000 cps to 400,000 cps, or from 25,000cps to 350,000 cps, or from 25,000 cps to 300,000 cps, or from 50,000cps to 500,000 cps, or from 50,000 cps to 400,000 cps, or from 50,000cps to 350,000 cps, or from 50,000 cps to 300,000 cps, or from 75,000cps to 500,000 cps, or from 75,000 cps to 400,000 cps, or from 75,000cps to 350,000 cps, or from 75,000 cps to 300,000 cps, or from 100,000cps to 500,000 cps, or from 100,000 cps to 400,000 cps, or from 100,000cps to 350,000 cps, or from 100,000 cps to 300,000 cps using aBrookfield RV viscometer on a helipath stand with the helipath on, witha T-E spindle at 10 RPM at room temperature for 45 seconds.

In another aspect, the invention relates to compositions that inhibitcrystal growth of taxane nanoparticles in carriers. In some embodiments,inhibition of crystal growth of taxane nanoparticles in carriers isaccomplished by inclusion of the nanoparticles in a hydrophobic carrier.In some embodiments, the hydrophobic carriers comprise a hydrocarbon. Insome embodiments, the hydrophobic carriers comprise petrolatum, mineraloil, and/or paraffin. In some embodiments, the mineral oil is heavymineral oil. In other embodiments, the hydrophobic carriers furthercomprise one or more volatile silicone fluids. In still otherembodiments, the volatile silicone fluid is cyclomethicone. In otherembodiments, the cyclomethicone is cyclopentasiloxane. In otherembodiments, inhibition of crystal growth of taxane nanoparticles inaqueous carriers is accomplished by inclusion of the nanoparticles in anaqueous carrier comprising poloxamer 407, a quaternary ammoniumcompound, or a cross-linked acrylic acid polymer, or mixtures thereof.

The compositions of the present invention can be formulated in variousforms suitable for pharmaceutical and topical delivery. Non-limitingexamples include semi-solid compositions, lotions, liquid suspensions,emulsions, creams, gels, ointments, pastes, aerosol sprays, aerosolfoams, non-aerosol sprays, non-aerosol foams, films, and sheets.Semi-solid compositions include ointments, pastes, and creams. Forpurposes of this invention, semi-solid compositions are not sprayable.The compositions can be impregnated in gauzes, bandages, or other skindressing materials. In some embodiments, the compositions are semi-solidcompositions. In some embodiments, the compositions are ointments. Inother embodiments, the compositions are gels. In still otherembodiments, the compositions are liquid suspensions. In someembodiments, the compositions are not sprays and are not sprayable.

The compositions of the present invention can be packaged in any packageconfiguration suitable for topical products. Non-limiting examplesinclude bottles, bottles with pumps, tottles, tubes (aluminum, plasticor laminated), jars, non-aerosol pump sprayers, aerosol containers,pouches, and packets. The packages can be configured for single-dose ormultiple-dose administration.

In various embodiments, the compositions of the invention arehydrophobic. In other embodiments, the hydrophobic compositions areanhydrous. In various embodiments, the hydrophobic carriers arenon-polar and/or non-volatile. In still other embodiments, thecompositions are aqueous based. In other embodiments, the compositionsof the invention are sterile. In other embodiments, the hydrophobiccompositions are non-sterile. In other embodiments, the hydrophobiccompositions have a low bioburden. In various embodiments, thehydrophobic compositions of the invention do not contain additional skinpenetration enhancers. In other embodiments, the hydrophobiccompositions of the invention do not contain additional volatilesolvents. In still other embodiments, the hydrophobic compositions ofthe invention do not contain surfactants. In other embodiments, thehydrophobic compositions of the invention do not contain alcohols, C₁-C₄aliphatic alcohols, or C₁-C₅ aliphatic alcohols.

A. Taxane Nanoparticles

Taxanes are poorly water soluble drugs having a solubility of less thanor equal to 10 mg/mL in water at room temperature. Taxanes are widelyused as chemotherapy agents. The term “taxanes” as used herein includepaclitaxel (I), docetaxel (II), cabazitaxel (III), and/or any othertaxane derivatives.

The taxane nanoparticles can be paclitaxel nanoparticles, docetaxelnanoparticles, or cabazitaxel nanoparticles, or nanoparticles of othertaxane derivatives. Paclitaxel and docetaxel active pharmaceuticalingredients (APIs) are commercially available from Phyton Biotech LLC,Vancouver, Canada. The docetaxel API and nanoparticles contain not lessthan 90%, or not less than 95%, or not less than 97.5% docetaxelcalculated on the anhydrous, solvent-free basis. The paclitaxel API andnanoparticles contain not less than 90%, or not less than 95%, or notless than 97% paclitaxel calculated on the anhydrous, solvent-freebasis. Paclitaxel API and nanoparticles can be prepared from asemisynthetic chemical process or from a natural source such as plantcell fermentation or extraction. Paclitaxel is also sometimes referredto by the trade name TAXOL, although this is a misnomer because TAXOL isthe trade name of a solution of paclitaxel in polyoxyethylated castoroil and ethanol intended for dilution with a suitable parenteral fluidprior to intravenous infusion. Paclitaxel is a poorly water solubledrug. The solubility of paclitaxel in water is less than 0.05 ppm asdetermined experimentally by the solubility method described inExample 1. The taxane nanoparticles can be in a crystalline form or inan amorphous form or a combination of both.

In various embodiments of the present invention, the taxane orpaclitaxel nanoparticles are uncoated (neat) individual particles; thetaxane or paclitaxel nanoparticles are not bound to any substance; nosubstances are absorbed or adsorbed onto the surface of the taxane orpaclitaxel nanoparticles; the taxane or paclitaxel nanoparticles are notencapsulated in any substance; the taxane or paclitaxel nanoparticlesare not coated with any substance; the taxane or paclitaxelnanoparticles are not microemulsions, nanoemulsions, microspheres, orliposomes of a taxane or paclitaxel; the taxane or paclitaxel particlesare not bound to, encapsulated in, or coated with a monomer, a polymer(or biocompatible polymer), a protein, a surfactant, or albumin; and/ora monomer, a polymer (or biocompatible polymer), a protein, asurfactant, or albumin is not absorbed or adsorbed onto the surface ofthe taxane or paclitaxel nanoparticles. In some embodiments, thecompositions are free of/do not include or contain a polymer orbiocompatible polymer. In some embodiments, the compositions are freeof/do not include or contain a protein. In some aspects of theinvention, the compositions are free of/do not include or containalbumin. In some aspects of the invention, the compositions are freeof/do not include or contain hyaluronic acid. In some aspects of theinvention, the compositions are free of/do not include or contain aconjugate of hyaluronic acid and a taxane. In some aspects of theinvention, the compositions are free of/do not include or contain aconjugate of hyaluronic acid and paclitaxel. In some aspects of theinvention, the compositions are free of/do not include or containpoloxamers, styrene-isobutylene-styrene (SIBS), a polyanhydridecopolymer, polycaprolactone, polyethylene glycol, Poly(bis(P-carboxyphenoxy)propane-sebacic acid, and/or poly(D, Llactic-co-glycolic acid (PLGA).

The taxane nanoparticles, including paclitaxel nanoparticles, docetaxelnanoparticles, or cabazitaxel nanoparticles, can have a mean particlesize (number) of from 0.01 microns to 1.5 microns, or from 0.01 micronsto 1.2 microns, or from 0.01 microns to 1 micron, or from 0.01 micronsto less than 1 micron, or from 0.01 microns to 0.9 microns, or from 0.01microns to 0.8 microns, or from 0.01 microns to 0.7 microns, or from 0.1microns to 1.5 microns, or from 0.1 microns to 1.2 microns, or from 0.1microns to 1 micron, or from 0.1 microns to less than 1 micron, or from0.1 microns to 0.9 microns, or from 0.1 microns to 0.8 microns, or from0.1 to 0.7 microns, or from 0.2 microns to 1.5 microns, or from 0.2microns to 1.2 microns, or from 0.2 microns to 1 micron, or from 0.2microns to less than 1 micron, or from 0.2 microns to 0.9 microns, orfrom 0.2 microns to 0.8 microns, or from 0.2 microns to 0.7 microns, orfrom 0.3 microns to 1.5 microns, or from 0.3 microns to 1.2 microns, orfrom 0.3 microns to 1 micron, or from 0.3 microns to less than 1 micron,or from 0.3 microns to 0.9 microns, or from 0.3 microns to 0.8 microns,or from 0.3 microns to 0.7 microns, or from 0.4 microns to 1.5 microns,or from 0.4 microns to 1.2 microns, or from 0.4 microns to 1 micron, orfrom 0.4 microns to less than 1 micron, or from 0.4 microns to 0.9microns, or from 0.4 microns to 0.8 microns, or from 0.4 microns to 0.7microns, or from 0.5 microns to 1.5 microns, or from 0.5 microns to 1.2microns, or from 0.5 microns to 1 micron, or from 0.5 microns to lessthan 1 micron, or from 0.5 microns to 0.9 microns, or from 0.5 micronsto 0.8 microns, or form 0.5 microns to 0.7 microns, or from 0.6 micronsto 1.5 microns, or from 0.6 microns to 1.2 microns, or from 0.6 micronsto 1 micron, or from 0.6 microns to less than 1 micron, or from 0.6microns to 0.9 microns, or from 0.6 microns to 0.8 microns, or from 0.6microns to 0.7 microns.

The particle size of the taxane when incorporated in a composition isdetermined by a particle size analyzer instrument and the measurement isexpressed as the mean diameter based on a number distribution. Asuitable particle size analyzer instrument is one which employs theanalytical technique of light obscuration, also referred to as photozoneor single particle optical sensing (SPOS). A suitable light obscurationparticle size analyzer instrument is the ACCUSIZER available fromParticle Sizing Systems, Port Richey, Fla.

In various embodiments, the mean particle size of the taxanenanoparticles incorporated in a composition does not grow larger than20% of the initial mean particle size when the composition is stored atroom temperature for at least 1 month, or for at least 3 months, or forat least 6 months or for at least 12 months. The term “initial meanparticle size”, as used herein with regard to the particle size oftaxane nanoparticles, is the mean particle size of the taxaneincorporated in the composition when measured by a particle sizeanalyzer instrument within 45 days after the completion of manufactureof the composition (date of manufacture), and the initial mean particlesize is from 0.1 microns to 1.5 microns (number) or from 0.01 microns to1.5 microns (number).

Nanoparticles of taxanes can be manufactured using various particlesize-reduction methods and equipment known in the art. Such methodsinclude, but are not limited to, wet or dry milling, micronizing,disintegrating, pulverizing, and supercritical carbon dioxide particlesize reduction methods. In various embodiments, the taxane or paclitaxelnanoparticles are made by a supercritical carbon dioxide particlereduction method (also known as “precipitation with compressedanti-solvents” or “PCA”) as disclosed in U.S. Pat. Nos. 5,874,029,5,833,891, 6,113,795, 7,744,923, 8,778,181, US publication 2014/0296140,US publication 2016/0354336, US publication 2016/0374953, andinternational patent application publication WO 2016/197091 (applicationno. PCT/US16/35993) all of which are herein incorporated by reference.

In the supercritical carbon dioxide particle size reduction method,supercritical carbon dioxide (anti-solvent) and solvent, e.g. acetone orethanol, are employed to generate uncoated taxane nanoparticles within awell-characterized particle-size distribution. The carbon dioxide andacetone are removed during processing (up to 0.5% residual solvent mayremain), leaving taxane nanoparticle powder generally ranging in sizefrom about 200 nm to about 800 nm. Stability studies show that thepowder is stable in a vial dose form when stored at controlled roomtemperature (25° C./60% relative humidity) for up to 59 months and underaccelerated conditions (40° C./75% relative humidity) for up to sixmonths.

Taxane nanoparticles produced by various supercritical carbon dioxideparticle size reduction methods can have unique physical characteristicsas compared to taxane nanoparticles produced by conventional particlesize reduction methods using physical impacting or grinding, e.g., wetor dry milling, micronizing, disintegrating, comminuting,microfluidizing, or pulverizing. As disclosed in US publication2016/0354336 and international patent application publication WO2016/197091 all of which are herein incorporated by reference, suchunique characteristics include a bulk density (not tapped) between 0.05g/cm³ and 0.15 g/cm³ and a specific surface area (SSA) of at least 18m²/g of taxane (paclitaxel and docetaxel) nanoparticles, which areproduced by the supercritical carbon dioxide particle size reductionmethods described in US publication 2016/0354336 and internationalpatent application publication WO 2016/197091 and as described below.This bulk density range is generally lower than the bulk density oftaxane particles produced by conventional means, and the SSA isgenerally higher than the SSA of taxane particles produced byconventional means. These unique characteristics result in significantincreases in dissolution rates in water/methanol media as compared totaxanes produced by conventional means. As used herein, the “specificsurface area (SSA)” is the total surface area of the taxane nanoparticleper unit of taxane mass as measured by the Brunauer-Emmett-Teller(“BET”) isotherm by the following method: a known mass between 200 and300 mg of the analyte is added to a 30 mL sample tube. The loaded tubeis then mounted to a Porous Materials Inc. SORPTOMETER®, model BET-202A.The automated test is then carried out using the BETWIN® softwarepackage and the surface area of each sample is subsequently calculated.The bulk density measurement can be conducted by pouring the taxanenanoparticles into a graduated cylinder without tapping at roomtemperature, measuring the mass and volume, and calculating the bulkdensity.

As disclosed in US publication 2016/0354336 and international patentapplication publication WO 2016/197091, studies showed a SSA of 15.0m²/g and a bulk density of 0.31 g/cm³ for paclitaxel nanoparticlesproduced by milling paclitaxel in a Deco-PBM-V-0.41 ball mill suing a 5mm ball size, at 600 RPM for 60 minutes at room temperature. Alsodisclosed in US publication 2016/0354336 and international patentapplication publication WO 2016/197091, one lot of paclitaxelnanoparticles had a SSA of 37.7 m²/g and a bulk density of 0.085 g/cm³when produced by a supercritical carbon dioxide method using thefollowing method: a solution of 65 mg/ml of paclitaxel was prepared inacetone. A BETE MicroWhirl® fog nozzle (BETE Fog Nozzle, Inc.) and asonic probe (Qsonica, model number Q700) were positioned in thecrystallization chamber approximately 8 mm apart. A stainless steel meshfilter with approximately 100 nm holes was attached to thecrystallization chamber to collect the precipitated paclitaxelnanoparticles. The supercritical carbon dioxide was placed in thecrystallization chamber of the manufacturing equipment and brought toapproximately 1200 psi at about 38° C. and a flow rate of 24 kg/hour.The sonic probe was adjusted to 60% of total output power at a frequencyof 20 kHz. The acetone solution containing the paclitaxel was pumpedthrough the nozzle at a flow rate of 4.5 mL/minute for approximately 36hours. Additional lots of paclitaxel nanoparticles produced by thesupercritical carbon dioxide method described above had SSA values of:22.27 m²/g, 23.90 m²/g, 26.19 m²/g, 30.02 m²/g, 31.16 m²/g, 31.70 m²/g,32.59 m²/g, 33.82 m²/g, 35.90 m²/g, 38.22 m²/g, and 38.52 m²/g.

As disclosed in US publication 2016/0354336 and international patentapplication publication WO 2016/197091, studies showed a SSA of 15.2m²/g and a bulk density of 0.44 g/cm³ for docetaxel nanoparticlesproduced by milling docetaxel in a Deco-PBM-V-0.41 ball mill suing a 5mm ball size, at 600 RPM for 60 minutes at room temperature. Alsodisclosed in US publication 2016/0354336 and international patentapplication publication WO 2016/197091, docetaxel nanoparticles had aSSA of 44.2 m²/g and a bulk density of 0.079 g/cm³ when produced by asupercritical carbon dioxide method using the following method: Asolution of 79.32 mg/ml of docetaxel was prepared in ethanol. The nozzleand a sonic probe were positioned in the pressurizable chamberapproximately 9 mm apart. A stainless steel mesh filter withapproximately 100 nm holes was attached to the pressurizable chamber tocollect the precipitated docetaxel nanoparticles. The supercriticalcarbon dioxide was placed in the pressurizable chamber of themanufacturing equipment and brought to approximately 1200 psi at about38° C. and a flow rate of 68 slpm. The sonic probe was adjusted to 60%of total output power at a frequency of 20 kHz. The ethanol solutioncontaining the docetaxel was pumped through the nozzle at a flow rate of2 mL/minute for approximately 95 minutes). The precipitated docetaxelagglomerates and particles were then collected from the supercriticalcarbon dioxide as the mixture is pumped through the stainless steel meshfilter. The filter containing the nanoparticles of docetaxel was openedand the resulting product was collected from the filter.

As disclosed in US publication 2016/0354336 and international patentapplication publication WO 2016/197091, dissolution studies showed anincreased dissolution rate in methanol/water media of paclitaxel anddocetaxel nanoparticles made by the supercritical carbon dioxide methodsdescribed in US publication 2016/0354336 and international patentapplication publication WO 2016/197091 as compared to paclitaxel anddocetaxel nanoparticles made by milling paclitaxel and docetaxel using aDeco-PBM-V-0.41 ball mill suing a 5 mm ball size, at 600 RPM for 60minutes at room temperature. The procedures used to determine thedissolution rates are as follows. For paclitaxel, approximately 50 mg ofmaterial were coated on approximately 1.5 grams of 1 mm glass beads bytumbling the material and beads in a vial for approximately 1 hour.Beads were transferred to a stainless steel mesh container and placed inthe dissolution bath containing methanol/water 50/50 (v/v) media at 37°C., pH 7, and a USP Apparatus II (Paddle), operating at 75 rpm. At 10,20, 30, 60, and 90 minutes, a 5 mL aliquot was removed, filtered througha 0.22 μm filter and analyzed on a UV/VIS spectrophotometer at 227 nm.Absorbance values of the samples were compared to those of standardsolutions prepared in dissolution media to determine the amount ofmaterial dissolved. For docetaxel, approximately 50 mg of material wasplaced directly in the dissolution bath containing methanol/water 15/85(v/v) media at 37° C., pH 7, and a USP Apparatus II (Paddle), operatingat 75 rpm. At 5, 15, 30, 60, 120 and 225 minutes, a 5 mL aliquot wasremoved, filtered through a 0.22 μm filter, and analyzed on a UV/VISspectrophotometer at 232 nm. Absorbance values of the samples werecompared to those of standard solutions prepared in dissolution media todetermine the amount of material dissolved. For paclitaxel, thedissolution rate was 47% dissolved in 30 minutes for the nanoparticlesmade by the supercritical carbon dioxide method versus 32% dissolved in30 minutes for the nanoparticles made by milling. For docetaxel, thedissolution rate was 27% dissolved in 30 minutes for the nanoparticlesmade by the supercritical carbon dioxide method versus 9% dissolved in30 minutes for the nanoparticles made by milling.

In some embodiments, the paclitaxel nanoparticles have an SSA of atleast 18, at least 19, at least 20, at least 21, at least 22, at least23, at least 24, at least 25, at least 26, at least 27, at least 28, atleast 29, at least 30, at least 31, at least 32, at least 33, at least34, or at least 35 m²/g. In other embodiments, the paclitaxelnanoparticles have an SSA of 18 m²/g to 50 m²/g, or 20 m²/g to 50 m²/g,or 22 m²/g to 50 m²/g, or 25 m²/g to 50 m²/g, or 30 m²/g to 50 m²/g, or18 m²/g to 45 m²/g, or 20 m²/g to 45 m²/g, or 22 m²/g to 45 m²/g, or 25m²/g to 45 m²/g, or 30 m²/g to 45 m²/g, or 18 m²/g to 40 m²/g, or 20m²/g to 40 m²/g, or 22 m²/g to 40 m²/g, or 25 m²/g to 40 m²/g, or 30m²/g to 40 m²/g.

In some embodiments, the paclitaxel nanoparticles have a bulk density(not-tapped) of 0.05 g/cm³ to 0.15 g/cm³, or 0.05 g/cm³ to 0.20 g/cm³.

In some embodiments, the paclitaxel nanoparticles have a dissolutionrate of at least 40% w/w dissolved in 30 minutes or less in a solutionof 50% methanol/50% water (v/v) in a USP II paddle apparatus operatingat 75 RPM, at 37° C., and at a pH of 7.

In some embodiments, the docetaxel nanoparticles have an SSA of at least18, at least 19, at least 20, at least 21, at least 22, at least 23, atleast 24, at least 25, at least 26, at least 27, at least 28, at least29, at least 30, at least 31, at least 32, at least 33, at least 34, atleast 35, at least 36, at least 37, at least 38, at least 39, at least40, at least 41, or at least 42 m²/g. In other embodiments, thedocetaxel nanoparticles have an SSA of 18 m²/g to 60 m²/g, or 22 m²/g to60 m²/g, or 25 m²/g to 60 m²/g, or 30 m²/g to 60 m²/g, or 40 m²/g to 60m²/g, or 18 m²/g to 50 m²/g, or 22 m²/g to 50 m²/g, or 25 m²/g to 50m²/g, or 30 m²/g to 50 m²/g, or 40 m²/g to 50 m²/g.

In some embodiments, the docetaxel nanoparticles have a bulk density(not-tapped) of 0.05 g/cm³ to 0.15 g/cm³.

In some embodiments, the docetaxel nanoparticles have a dissolution rateof at least 20% w/w dissolved in 30 minutes or less in a solution of 15%methanol/85% water (v/v) in a USP II paddle apparatus operating at 75RPM, at 37° C., and at a pH of 7.

It was found that paclitaxel nanoparticle crystals have a tendency togrow in suspensions of water or saline solutions over time forming largeneedle-like crystals. A crystal growth study was conducted and theresults are shown in Table 2 in Example 2 below. It was found that thenanoparticles crystals did not grow in the hydrophobic materials. Also,and surprisingly, the nanoparticle crystals did not grow in aqueoussolutions of benzalkonium chloride, CARBOPOL ULTREZ 10, or poloxamer407.

B. Hydrophobic Carriers

The hydrophobic carriers of the present invention can comprisesubstances from plant, animal, paraffinic, and/or synthetically derivedsources. Hydrophobic substances are generally known as substances thatlack an affinity for and repel water. The hydrophobic carrier can be thecontinuous phase of the compositions. In various embodiments, thehydrophobic carriers are non-polar and/or non-volatile. Non-limitingexamples include fats, butters, greases, waxes, solvents, and oils;mineral oils; vegetable oils; petrolatums; water insoluble organicesters and triglycerides; and fluorinated compounds. The hydrophobiccarriers can also comprise silicone materials. Silicone materials aredefined as compounds based on polydialkylsiloxanes and include polymers,elastomers (crosslinked silicones), and adhesives (branched silicones).Non-limiting examples of silicone materials include dimethicone(polydimethylsiloxane), dimethicone copolyol, cyclomethicone,simethicone, silicone elastomers such as ST-elastomer 10 (DOW CORNING),silicone oils, silicone polymers, volatile silicone fluids, and siliconewaxes. In some embodiments, the hydrophobic carrier does not comprisesilicone materials.

Plant derived materials include, but are not limited to, arachis(peanut) oil, balsam Peru oil, carnauba wax, candellila wax, castor oil,hydrogenated castor oil, cocoa butter, coconut oil, corn oil, cottonseed oil, jojoba oil, macadamia seed oil, olive oil, orange oil, orangewax, palm kernel oil, rapeseed oil, safflower oil, sesame seed oil, sheabutter, soybean oil, sunflower seed oil, tea tree oil, vegetable oil,and hydrogenated vegetable oil.

Non-limiting examples of animal derived materials include beeswax(yellow wax and white wax), cod liver oil, emu oil, lard, mink oil,shark liver oil, squalane, squalene, and tallow. Non-limiting examplesof paraffinic materials include isoparaffin, microcrystalline wax, heavymineral oil, light mineral oil, ozokerite, petrolatum, white petrolatum,and paraffin wax.

Non-limiting examples of organic esters and triglycerides include C12-15alkyl benzoate, isopropyl myristate, isopropyl palmitate, medium chaintriglycerides, mono- and di-glycerides, trilaurin, andtrihydroxystearin.

A non-limiting example of a fluorinated compound is perfluoropolyether(PFPE), such as FOMBLIN® HC04 commercially available from SolvaySpecialty Polymers.

The hydrophobic carriers of the present invention can comprisepharmaceutical grade hydrophobic substances. In various embodiments ofthe present invention the hydrophobic carriers comprise petrolatum,mineral oil, or paraffin, or mixtures thereof. In some embodiments, themineral oil is heavy mineral oil.

In some embodiments, the concentration of the hydrophobic carrier in thecompositions is greater than 10% w/w of the total composition weight. Inother embodiments, the concentration of the hydrophobic carrier in thecompositions is greater than 15%, or greater than 20%, or greater than25%, or greater than 30%, or greater than 35%, or greater than 40%, orgreater than 45%, or greater than 50%, or greater than 55%, or greaterthan 60%, or greater than 65%, or greater than 70%, or greater than 75%,or greater than 80%, or greater than 82%, or greater than 85%, orgreater than 87%, or greater than 90% w/w of the total compositionweight. In other embodiments, the concentration of the hydrophobiccarrier in the compositions is from greater than 10% w/w to 95% w/w ofthe total composition weight. In other embodiments, the concentration ofthe hydrophobic carrier in the compositions is from 11% w/w to 95% w/w,or from 12% w/w to 95% w/w, or from 13% w/w to 95% w/w, or from 14% w/wto 95% w/w, or from 15% w/w to 95% w/w, or from 16% w/w to 95% w/w, orfrom 17% w/w to 95% w/w, or from 18% w/w to 95% w/w, or from 19% w/w to95% w/w, or from 20% w/w to 95% w/w of the total composition weight.

(i) Petrolatum

Petrolatum is a purified mixture of semi-solid saturated hydrocarbonsobtained from petroleum, and varies from dark amber to light yellow incolor. White petrolatum is wholly or nearly decolorized and varies fromcream to snow white in color. Petrolatums are available with differentmelting point, viscosity, and consistency characteristics. Petrolatumsmay also contain a stabilizer such as an antioxidant. Pharmaceuticalgrades of petrolatum include Petrolatum USP and White Petrolatum USP.

Various petrolatums are available commercially from the PenrecoCorporation under the trade names: ULTIMA, SUPER, SNOW, REGENT, LILY,CREAM, ROYAL, BLOND, and AMBER. Various grades of petrolatum are alsoavailable commercially from the Sonneborn Corporation under the tradenames: ALBA, SUPER WHITE PROTOPET, SUPER WHITE FONOLINE, WHITE PROTOPET1S, WHITE PROTOPET 2L, WHITE PROTOPET 3C, WHITE FONOLINE, PERFECTA,YELLOW PROTOPET 2A, YELLOW FONOLINE, PROTOLINE, SONOJELL #4, SONOJELL#9, MINERAL JELLY #10, MINERAL JELLY #14, MINERAL JELLY #17, ANDCARNATION TROUGH GREASE. Petrolatums are also available from theSpectrum Chemical Mfg. Corp.

(ii) Mineral Oil

Mineral oil is a mixture of liquid hydrocarbons obtained from petroleum.Mineral oil is available in various viscosity grades, such as lightmineral oil, heavy mineral oil, and extra heavy mineral oil. Lightmineral oil has a kinematic viscosity of not more than 33.5 centistokesat 40° C. Heavy mineral oil has a kinematic viscosity of not less than34.5 centistokes at 40° C. Mineral oil may contain a suitablestabilizer. Pharmaceutical grades of mineral oil include Mineral OilUSP, which is heavy mineral oil, and Light Mineral Oil NF, which islight mineral oil. Mineral oil is commercially available from thePenreco Corporation under the DRAKEOL trade name, and the SonnebornCorporation under the trade names BENOL, BLANDOL, BRITOL, CARNATION,ERVOL, GLORIA, KAYDOL, KLEAROL, PROTOL, and RUDOL. Mineral oil is alsocommercially available from the Spectrum Chemical Mfg. Corp.

(iii) Paraffin Wax

Paraffin wax is a purified mixture of solid hydrocarbons obtained frompetroleum. It may also be synthetically derived by the Fischer-Tropschprocess from carbon monoxide and hydrogen which are catalyticallyconverted to a mixture of paraffin hydrocarbons. Paraffin wax maycontain an antioxidant. Pharmaceutical grades of paraffin wax includeParaffin NF and Synthetic Paraffin NF. Paraffin waxes are commerciallyavailable from the Spectrum Chemical Mfg. Corp, Koster Keunen, Inc. andFrank B. Ross, Inc.

C. Volatile Silicone Fluids

Volatile silicone fluids, also known as volatile silicone oils, arevolatile liquid polysiloxanes which can by cyclic or linear. They areliquid at room temperature. Volatile silicone fluids are hydrophobicmaterials. Linear volatile silicone fluids include polydimethylsiloxane,hexamethyldisiloxane and octamethyltrisiloxane and are commerciallyavailable from Dow Corning under the trade names DOW CORNING Q7-9180Silicone Fluid 0.65 cSt and DOW CORNING Q7-9180 Silicone Fluid 1.0 cSt,respectively. Cyclic volatile silicone fluids are generally known ascyclomethicones.

(i) Cyclomethicone

Cyclomethicone is a fully methylated cyclic siloxane containingrepeating units of formula (IV):[—(CH₃)₂SiO—]_(n)  (IV)in which n is 3, 4, 5, 6, or 7; or mixtures thereof. Cyclomethicone is aclear, colorless volatile liquid silicone fluid. Cyclomethicone hasemollient properties and helps to improve the tactile feel of an oilbased product by making it feel less greasy on the skin. Pharmaceuticalgrade cyclomethicone includes Cyclomethicone NF. Cyclomethicone NF isrepresented by formula (IV) in which n is 4 (cyclotetrasiloxane), 5(cyclopentasiloxane), or 6 (cyclohexasiloxane); or mixtures thereof.Cyclopentasiloxane, also known as decamethylcylcopentasiloxane,cyclomethicone D5, or cyclomethicone 5, is the cyclomethiconerepresented by formula (IV) in which n is 5 (pentamer), but it cancontain small amounts (generally less than 1%) of one or more of theother cyclic chain length cyclomethicones. Cyclopentasiloxane isavailable in a pharmaceutical grade as Cyclomethicone NF.Cyclomethicones are commercially available from Dow Corning under thetrade names DOW CORNING ST-Cyclomethicone 5-NF, DOW CORNINGST-Cyclomethicone 56-NF, and XIAMETER PMX-0245. It is also commerciallyavailable from the Spectrum Chemical Mfg. Corp. Cyclopentasiloxane has avapor pressure of about 20 to about 27 Pa at 25° C.

In one embodiment, the concentration of cyclomethicone in thecomposition is less than 25% w/w. In another embodiment, thecyclomethicone in the composition is at a concentration from 5 to 24%w/w. In another embodiment, the concentration of cyclomethicone is from5 to 20% w/w. In another embodiment, the cyclomethicone is at aconcentration of from 5 to 18% w/w. In another embodiment, theconcentration of cyclomethicone is 13% w/w. In various embodiments, theconcentration of cyclomethicone can be 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5,9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16,16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23,23.5, or 24% w/w or any percentage derivable therein of the totalcomposition weight. In one embodiment, the cyclomethicone iscyclopentasiloxane.

D. Aqueous Based Compositions

Aqueous based compositions of the invention comprise taxanenanoparticles and an aqueous carrier. The aqueous formulations aredispersions (suspensions) of the taxane nanoparticles in an aqueouscarrier. The taxane nanoparticles can be completely dispersed, partiallydispersed and partially dissolved, but not completely dissolved in theaqueous carrier. An aqueous based composition is a composition in whichwater is the major constituent. Aqueous carriers can include singlephase aqueous solutions, and multi-phase aqueous based emulsions suchoil-in-water and water-in-oil emulsions.

It was observed that taxane nanoparticle crystals, such as paclitaxelnanoparticles, rapidly grew in water and in aqueous based carriers. Inmany cases, the growth was observed in as little as 3 days at roomtemperature, and some cases in 24 hours. Many of the crystals wereneedle-like in shape and were larger than 5 μm in length. A study wasconducted and the results are shown in Table 2 in Example 2.Surprisingly, the taxane nanoparticle crystal growth was inhibited bythe addition of poloxamer 407, a quaternary ammonium compound, or across-linked acrylic acid polymer to the aqueous based carrier duringprocessing. The addition of poloxamer 188 did not inhibit the growth ofthe nanoparticle crystals.

It was also observed that the presence of a quaternary ammoniumcompound, or a cross-linked acrylic acid polymer, or mixtures thereof inan aqueous carrier comprising taxane nanoparticle crystals preventedgrowth of the nanoparticle crystals over time. A study was conducted andthe results are shown in Table 11 in Example 8 revealing that the meanparticle size of poorly water soluble taxane nanoparticles (paclitaxel)in an aqueous composition comprising poloxamer 407, a quaternaryammonium compound, or a cross-linked acrylic acid polymer, or mixturesthereof does not grow larger than 20% of the initial mean particle sizewhen the aqueous composition is stored at room temperature for 6 months.In some embodiments, there is disclosed an aqueous based compositioncomprising an aqueous carrier; a plurality of taxane nanoparticles; anda quaternary ammonium compound, or a cross-linked acrylic acid polymer,or mixtures thereof; wherein the mean particle size of the taxanenanoparticles is from 0.1 microns to 1.5 microns (number) or from 0.01microns to 1.5 microns (number), and wherein the mean particle size ofthe taxane nanoparticles does not grow larger than 20% of the initialmean particle size when the composition is stored at room temperaturefor at least 6 months. In other embodiments, the composition furthercomprises poloxamer 407.

In one aspect of the invention, disclosed are compositions comprisingtaxane nanoparticles, an aqueous carrier, and poloxamer 407, aquaternary ammonium compound, or a cross-linked acrylic acid polymer, ormixtures thereof. It was surprisingly found that the addition ofpoloxamer 407, a quaternary ammonium compound, or a cross-linked acrylicacid polymer inhibited the crystal growth of the taxane nanoparticles inaqueous carriers. The aqueous based compositions of the invention aresuitable for topical, injectable, (IV) infusion, or oral liquid dosageforms. In one embodiment, the additive to inhibit crystal growth ispoloxamer 407. In various embodiments, the quaternary ammonium compoundis the additive to inhibit crystal growth and is benzalkonium chlorideor benzethonium chloride. In other embodiments, the quaternary ammoniumcompound is benzalkonium chloride. In other embodiments, thecross-linked acrylic acid polymer is the additive to inhibit crystalgrowth and is Carbomer.

In one aspect of the invention, the composition comprises poloxamer 407and taxane nanoparticles in an aqueous carrier suitable for injectiondelivery including (IV) infusion. In various embodiments, the taxanenanoparticles are docetaxel nanoparticles, paclitaxel nanoparticles, orcabazitaxel nanoparticles.

In another aspect of the invention, the composition comprises aquaternary ammonium compound and taxane nanoparticles in an aqueouscarrier suitable for injection delivery including (IV) infusion. Invarious embodiments, the taxane nanoparticles are docetaxelnanoparticles, paclitaxel nanoparticles, or cabazitaxel nanoparticles.In other embodiments, the quaternary ammonium compounds are benzalkoniumchloride or benzethonium chloride.

In one aspect of the invention, disclosed are methods of inhibiting thegrowth of a dispersion of crystalline taxane nanoparticles in an aqueousbased carrier, the method comprising adding poloxamer 407, a quaternaryammonium compound, or a cross-linked acrylic acid polymer, or mixturesthereof, to the aqueous based carrier during processing, wherein themean particle size of the taxane nanoparticles is from 0.1 microns to1.5 microns (number) or from 0.01 microns to 1.5 microns (number). Insome embodiments, the quaternary ammonium compound is benzalkoniumchloride or benzethonium chloride. In some embodiments, the cross-linkedacrylic acid polymer is carbomer. In some embodiments, the taxanenanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, orcabazitaxel nanoparticles. In still other embodiments, the taxanenanoparticles are paclitaxel nanoparticles.

(i) Poloxamer 407

Poloxamer 407 is a solid, hydrophilic, nonionic, synthetic blockcopolymer of ethylene oxide and propylene oxide conforming to thegeneral formula (V)HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H  (V)where a is 101 and b is 56. Poloxamer 407 has an average molecularweight of 9840-14600. The term “poloxamer” is the nonproprietary name ofthe copolymer. Poloxamers are available in several types which havevarious physical forms and various average molecular weights. Eachspecific poloxamer type is identified by the nonproprietary name“poloxamer” followed by a three digit number, the first two digits ofwhich when multiplied by 100 correspond to the approximate averagemolecular weight of the polyoxypropylene portion of the copolymer; andthe third digit, when multiplied by 10, corresponds to the percentage byweight of the polyoxyethylene portion. Poloxamers are available inpharmaceutical, cosmetic, and industrial grades. Pharmaceutical gradepoloxamers are listed in recognized pharmaceutical compendia such asUSP/NF and European Pharmacopeia (PhEur). According to the USP/NF andPhEur, a suitable antioxidant may be added. Poloxamer 407 iscommercially available from BASF under the trade name PLURONIC® F127.The addition of poloxamer 188 to an aqueous carrier did not inhibitcrystal growth of the taxane nanoparticles. Suitable concentrations ofPoloxamer 407 are at least 2% w/w, or from 0.1 to 25% w/w, or from 0.1to 20% w/w, or from 0.1 to 15% w/w, or from 0.1 to 10% w/w, or from 1 to25% w/w, or from 1 to 20% w/w, or from 1 to 15% w/w, or from 1 to 10%w/w, or from 2 to 25% w/w, or from 2 to 20% w/w, or from 2 to 15% w/w,or from 2 to 10% w/w.

(ii) Quaternary Ammonium Compounds

Quaternary ammonium compounds (including salts) are positively chargedtetra-substituted nitrogen derivatives of formula (VI)

in which R¹, R², R³, and R⁴ may be the same or different, but may not behydrogen. X⁻ represents a typical anion such as chloride. Suitablequaternary ammonium compounds include benzalkonium chloride andbenzethonium chloride. Benzalkonium chloride is commercially availablein a 100% powder or a 50% aqueous solution. Other examples of quaternaryammonium compounds are disclosed in the International CosmeticIngredient Dictionary and Handbook, 12th edition, 2008 hereinincorporated by reference. Suitable concentrations of quaternaryammonium compounds are at least 0.05% w/w, or at least 0.1% w/w, or atleast 1% w/w, or at least 2% w/w, or from 0.05 to 5% w/w, or from 0.1 to5% w/w, or from 1 to 5% w/w, or from 2 to 5% w/w.

(iii) Cross-Linked Acrylic Acid Polymers

Cross-linked acrylic acid polymers are high molecular weight homo- andco-polymers of acrylic acid cross-linked with a polyalkenyl polyether.Suitable cross-linked acrylic acid polymers include Carbomer (INCIname), Acrylates Copolymer (INCI name), Acrylates/C10-30 Alkyl AcrylateCrosspolymer (INCI name), Acrylates Crosspolymer-4 (INCI name), andPolyacrylate-1 Crosspolymer (INCI name). The above mentioned polymersare all commercially available from the Lubrizol Corporation under theCARBOPOL® trade name. Examples of Carbomer available from the LubrizolCorporation include CARBOPOL 934, CARBOPOL 934P, CARBOPOL 940, CARBOPOL980, CARBOPOL 941, CARBOPOL 981, CARBOPOL 2984, CARBOPOL 5984, CARBOPOLSILK 100, CARBOPOL ETD 2050, ULTREZ 10, and ULTREZ 30. Examples ofAcrylates Copolymer available from the Lubrizol Corporation includeCARBOPOL AQUA SF-1, and CARBOPOL AQUA SF-1 OS. Examples ofAcrylates/C10-30 Alkyl Acrylate Crosspolymer available from the LubrizolCorporation include CARBOPOL ULTREZ 20, CARBOPOL ULTREZ 21, CARBOPOL ETD2020, CARBOPOL 1342, CARBOPOL 1382, and CARBOPOL SC-200. An example ofAcrylates Crosspolymer-4 is CARBOPOL AQUA SF-2. An example ofPolyacrylate-1 Crosspolymer is CARBOPOL AQUA CC. Suitable concentrationsof cross-linked acrylic acid polymers are at least 0.1% w/w, or 0.5%w/w, or from 0.1 to 5% w/w, or from 0.5 to 5% w/w.

E. Additional Ingredients and Adjuvants

The compositions of the invention can further comprise functionalingredients suitable for use in pharmaceutical compositions.Non-limiting examples include absorbents, acidifying agents,antimicrobial agents, antioxidants, binders, biocides, buffering agents,bulking agents, crystal growth inhibitors, chelating agents, colorants,deodorant agents, emulsion stabilizers, film formers, fragrances,humectants, lytic agents, enzymatic agents, opacifying agents, oxidizingagents, pH adjusters, plasticizers, preservatives, reducing agents,emollient skin conditioning agents, humectant skin conditioning agents,moisturizers, surfactants, emulsifying agents, cleansing agents, foamingagents, hydrotopes, solvents, suspending agents, viscosity controlagents (rheology modifiers), viscosity increasing agents (thickeners),and propellants. Listings and monographs of the examples of thefunctional ingredients described herein are disclosed in TheInternational Cosmetic Ingredient Dictionary and Handbook (INCI),12^(th) Edition, 2008, herein incorporated by reference.

The compositions of the invention can further comprise additionalpharmaceutically active ingredients, cosmetically active ingredients,and veterinary agents suitable for topical use.

Although, the hydrophobic compositions of the present invention canfurther comprise additional penetration enhancers, it was found that itwas not necessary to include additional penetration enhancers toincrease the skin penetration (i.e., into the epidermal and dermalportions of skin) of the taxane nanoparticles in hydrophobiccompositions comprising a hydrophobic carrier and one or more volatilesilicone fluids. In fact, the additions of skin penetration enhancershad little or no effect on the skin penetration of the hydrophobiccompositions.

The term “penetration enhancer” has been used to describe compounds ormaterials or substances that facilitate drug absorption through theskin. These compounds or materials or substances can have a directeffect on the permeability of the skin, or they can augment percutaneousabsorption by increasing the thermodynamic activity of the penetrant,thereby increasing the effective escaping tendency and concentrationgradient of the diffusing species. The predominant effect of theseenhancers is to either increase the stratum corneum's degree ofhydration or disrupt its lipoprotein matrix, the net result in eithercase being a decrease in resistance to drug (penetrant) diffusion(Remington, The Science and Practice of Pharmacy, 22^(nd) ed.).

Non-limiting examples of skin penetration enhancers include oleylalcohol, isopropyl myristate, dimethyl isosorbide (DMI) available underthe tradename ARLASOLVE DMI, and Diethylene Glycol Monoethyl Ether(DGME) which is available under the trade name TRANSCUTOL P. Otherexamples of skin penetration enhancers can be found in “Skin PenetrationEnhancers Cited in the Technical Literature”, Osborne, David W., andHenke, Jill J., Pharmaceutical Technology, November 1997, hereinincorporated by reference. Such examples include: Fatty alcohols such asaliphatic alcohols, Decanol, Lauryl alcohol (dodecanol), Linolenylalcohol, Nerolidol, 1-Nonanol, n-Octanol, Oleyl alcohol, Fatty acidesters, Butylacetate, Cetyl lactate, Decyl N,N-dimethylamino acetate,Decyl N,N-dimethylamino isopropionate, Diethyleneglycol oleate, Diethylsebacate, Diethyl succinate, Diisopropyl sebacate, DodecylN,N-dimethylamino acetate, Dodecyl (N,N-dimethylamino)-butyrate, DodecylN,N-dimethylamino isopropionate, Dodecyl 2-(dimethylamino) propionate,EO-5-oleyl ester, Ethyl acetate, Ethylaceto acetate, Ethyl propionate,Glycerol monoethers, Glycerol monolaurate, Glycerol monooleate, Glycerolmonolinoleate, Isopropyl isostearate, Isopropyl linoleate, Isopropylmyristate, Isopropyl myristate/fatty acid monoglyceride combination,Isopropyl myristate/ethanol/L-lactic acid (87:10:3) combination,Isopropyl palmitate, Methyl acetate, Methyl caprate, Methyl laurate,Methyl propionate, Methyl valerate, 1-Monocaproyl glycerol,Monoglycerides (medium chain length), Nicotinic esters (benzyl), Octylacetate, Octyl N,N-dimethylamino acetate, Oleyl oleate, n-PentylN-acetylprolinate, Propylene glycol monolaurate, Sorbitan dilaurate,Sorbitan dioleate, Sorbitan monolaurate, Sorbitan monooleates, Sorbitantrilaurate, Sorbitan trioleate, Sucrose coconut fatty ester mixtures,Sucrose monolaurate, Sucrose monooleate, and TetradecylN,N-dimethylamino acetate; Fatty acids such as Alkanoic acids, Capricacid, Diacid, Ethyloctadecanoic acid, Hexanoic acid, Lactic acid, Lauricacid, Linoelaidic acid, Linoleic acid, Linolenic acid, Neodecanoic acid,Oleic acid, Palmitic acid, Pelargonic acid, Propionic acid, and Vaccenicacid; Fatty alcohol ethers such as α-Monoglyceryl ether, EO-2-oleylether, EO-5-oleyl ether, EO-10-oleyl ether, and Ether derivatives ofpolyglycerols and alcohols(1-O-dodecyl-3-O-methyl-2-O-(2′,3′-dihydroxypropyl) glycerol); Biologicssuch as L-α-amino-acids, Lecithin, Phospholipids, Saponin/phospholipids,Sodium deoxycholate, Sodium taurocholate, and Sodium tauroglycocholate;Enzymes such as Acid phosphatase, Calonase, Orgelase, Papain,Phospholipase A-2, Phospholipase C, and Triacylglycerol hydrolase;Amines and Amides such as Acetamide derivatives, Acyclic amides,N-Adamantyl n-alkanamides, Clofibric acid amides, N,N-Didodecylacetamide, Di-2-ethylhexylamine, Diethyl methyl benzamide,N,N-Diethyl-m-toluamide, N,N-Dimethyl-m-toluarnide, Ethomeen S12[bis-(2-hydroxyethyl) oleylamine], Hexamethylene lauramide, Lauryl-amine(dodecylamine), Octyl amide, Oleylamine, Unsaturated cyclic ureas, andUrea; Complexing Agents such as, β- and γ-cyclodextrin complexes,Hydroxypropyl methylcellulose, Liposomes, Naphthalene diamide diimide,and Naphthalene diester diimide; Macrocyclics such as Macrocycliclactones, ketones, and anhydrides (optimum ring-16), and Unsaturatedcyclic ureas; Classical surfactants such as Brij 30, Brij 35, Brij 36T,Brij 52, Brij 56, Brij 58, Brij 72, Brij 76, Brij 78, Brij 92, Brij 96,Brij 98, Cetyl trimethyl ammonium bromide, Empicol ML26/F, HCO-60surfactant, Hydroxypolyethoxydodecane, Ionic surfactants (ROONa,ROSO₃Na, RNH₃Cl, R=8-16), Lauroyl sarcosine, Nonionic surface activeagents, Nonoxynol, Octoxynol, Phenylsulfonate CA, Pluronic F68, PluronicF 127, Pluronic L62, Polyoleates (nonionic surfactants), Rewopal HV 10,Sodium laurate, Sodium Lauryl sulfate (sodium dodecyl sulfate), Sodiumoleate, Sorbitan dilaurate, Sorbitan dioleate, Sorbitan monolaurate,Sorbitan monooleates, Sorbitan trilaurate, Sorbitan trioleate, Span 20,Span 40, Span 85, Synperonic NP, Triton X-100, Tween 20, Tween 40, Tween60, Tween 80, and Tween 85; N-methyl pyrrolidone and related compoundssuch as N-Cyclohexyl-2-pyrrolidone, 1-Butyl-3-dodecyl-2-pyrrolidone,1,3-Dimethyl-2-imidazolikinone, 1,5 Dimethyl-2-pyrrolidone,4,4-Dimethyl-2-undecyl-2-oxazoline, 1-Ethyl-2-pyrrolidone,1-Hexyl-4-methyloxycarbonyl-2-pyrrolidone, 1-Hexyl-2-pyrrolidone,1-(2-Hydroxyethyl) pyrrolidinone, 3-Hydroxy-N-methyl-2-pyrrolidinone,1-Isopropyl-2-undecyl-2-imidazoline,1-Lauryl-4-methyloxycarbonyl-2-pyrrolidone, N-Methyl-2-pyrrolidone,Poly(N-vinylpyrrolidone), Pyroglutamic acid esters, and 2-Pyrrolidone(2-pyrrolidinone); Ionic compounds such as Ascorbate, Amphoteric cationsand anions, Calcium thioglycolate, Cetyl trimethyl ammonium bromide,3,5-Diiodosalicylate sodium, Lauroylcholine iodide, 5-Methoxysalicylatesodium, Monoalkyl phosphates, 2-PAM chloride, 4-PAM chloride(derivatives of N-methyl picolinium chloride), Sodium carboxylate, andSodium hyaluronate; Dimethyl sulfoxide and related compounds such asCyclic sulfoxides, Decylmethyl sulfoxide, Dimethyl sulfoxide (DMSO), and2-Hydroxyundecyl methyl sulfoxide; Solvents and related compounds suchas Acetone, n-Alkanes (chain length between 7 and 16),Cyclohexyl-1,1-dimethylethanol, Dimethylacetamide, Dimethyl formamide,Ethanol, Ethanol/d-limonene combination, 2-Ethyl-1,3-hexanediol,Ethoxydiglycol (TRANSCUTOL), Glycerol, Glycols, Lauryl chloride,Limonene, N-Methylformamide, 2-Phenylethanol, 3-Phenyl-1-propanol,3-Phenyl-2-propen-1-ol, Polyethylene glycol, Polyoxyethylene sorbitanmonoesters, Polypropylene glycol, Primary alcohols (tridecanol),Propylene glycol, Squalene, Triacetin, Trichloroethanol,Trifluoroethanol, Trimethylene glycol, and Xylene; Azone and relatedcompounds such as N-Acyl-hexahydro-2-oxo-1H-azepines,N-Alkyl-dihydro-1,4-oxazepine-5,7-diones, N-Alkylmorpholine-2,3-diones,N-Alkylmorpholine-3,5-diones, Azacycloalkane derivatives (-ketone,-thione), Azacycloalkenone derivatives,1-[2-(Decylthio)ethyl]azacyclopentan-2-one (HPE-101),N-(2,2-Dihydroxyethyl)dodecylamine, 1-Dodecanoylhexahydro-1-H-azepine,1-Dodecyl azacycloheptan-2-one (AZONE or laurocapram), N-Dodecyldiethanolamine, N-Dodecyl-hexahydro-2-thio-1H-azepine,N-Dodecyl-N-(2-methoxyethyl)acetamide, N-Dodecyl-N-(2-methoxyethyl)isobutyramide, N-Dodecyl-piperidine-2-thione, N-Dodecyl-2-piperidinone,N-Dodecyl pyrrolidine-3,5-dione, N-Dodecyl pyrrolidine-2-thione,N-Dodecyl-2-pyrrolidone, 1-Famesylazacycloheptan-2-one,1-Famesylazacyclopentan-2-one, 1-Geranylazacycloheptan-2-one,1-Geranylazacyclopentan-2-one, Hexahydro-2-oxo-azepine-1-acetic acidesters, N-(2-Hydroxyethyl)-2-pyrrolidone, 1-Laurylazacycloheptane,2-(1-Nonyl)-1,3-dioxolane, 1-N-Octylazacyclopentan-2-one,N-(1-Oxododecyl)-hexahydro-1H-azepine, N-(1-Oxododecyl)-morpholines,1-Oxohydrocarbyl-substituted azacyclohexanes,N-(1-Oxotetradecyl)-hexahydro-2-oxo-1H-azepine, andN-(1-Thiododecyl)-morpholines; and others such as Aliphatic thiols,Alkyl N,N-dialkyl-substituted amino acetates, Anise oil, Anticholinergicagent pretreatment, Ascaridole, Biphasic group derivatives, Bisabolol,Cardamom oil, 1-Carvone, Chenopodium (70% ascaridole), Chenopodium oil,1,8 Cineole (eucalyptol), Cod liver oil (fatty acid extract),4-Decyloxazolidin-2-one, Dicyclohexylmethylamine oxide, Diethylhexadecylphosphonate, Diethyl hexadecylphosphoramidate, N,N-Dimethyldodecylamine-N-oxide, 4, 4-Dimethyl-2-undecyl-2-oxazoline,N-Dodecanoyl-L-amino acid methyl esters, 1,3-Dioxacycloalkanes (SEPAs),Dithiothreitol, Eucalyptol (cineole), Eucalyptus oil, Eugenol, Herbalextracts, Lactam N-acetic acid esters, N-Hydroxyethalaceamide,N-Hydroxyethylacetamide, 2-Hydroxy-3-oleoyloxy-1-pyroglutamyloxypropane,Menthol, Menthone, Morpholine derivatives, N-Oxide, Nerolidol,Octyl-β-D-(thio)glucopyranosides, Oxazolidinones, Piperazinederivatives, Polar lipids, Polydimethylsiloxanes, Poly[2-(methylsulfinyl)ethyl acrylate], Polyrotaxanes,Polyvinylbenzyldimethylalkylammonium chloride, Poly(N-vinyl-N-methylacetamide), Sodium pyroglutaminate, Terpenes and azacyclo ringcompounds, Vitamin E (α-tocopherol), Vitamin E TPGS and Ylang-ylang oil.Additional examples of penetration enhancers not listed above can befound in “Handbook of Pharmaceutical Excipients”, Fifth edition, andinclude glycofurol, lanolin, light mineral oil, myristic acid,polyoxyethylene alky ethers, and thymol. Other examples of penetrationenhancers include ethanolamine, diethanolamine, triethanolamine,diethylene glycol, monoethyl ether, citric acid, succinic acid, borageoil, tetrahydropiperine (THP), methanol, ethanol, propanol, octanol,benzyl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, andpolyethylene glycol monolaurate.

Although the hydrophobic compositions of the invention can furthercomprise alcohols, it is not necessary for the compositions to containalcohols, C₁-C₄ aliphatic alcohols, or C₁-C₅ aliphatic alcohols. In someaspects of the invention, the compositions are free of/do not include orcontain C₁-C₄ aliphatic alcohols, or C₁-C₅ aliphatic alcohols.

Although the hydrophobic compositions of the invention can furthercomprise additional volatile solvents, it is not necessary for thehydrophobic compositions to contain additional volatile solvents.Volatile solvents are also known as “fugitive” solvents. Non-limitingexamples of volatile solvents include volatile alcohols, such as C₁ toC₄ aliphatic alcohols; and volatile C₁ to C₄ aliphatic ketones, such asacetone. In some aspects of the inventions, the compositions are freeof/do not include or contain volatile C₁ to C₄ aliphatic ketones. Insome aspects of the inventions, the compositions are free of/do notinclude or contain volatile C₁ to C₄ aliphatic alcohols.

Although the hydrophobic compositions of the invention can furthercomprise surfactants, it is not necessary for the hydrophobiccompositions to contain surfactants. The term “surfactant” or “surfaceactive agent” means a compound or material or substance that exhibitsthe ability to lower the surface tension of water or to reduce theinterfacial tension between two immiscible substances and includesanionic, cationic, nonionic, amphoteric, and/or phospholipidsurfactants. Non-limiting examples of surfactants can be found inMcCutcheon's Emulsifiers & Detergents, 2001 North American Editionherein incorporated by reference and also in the International CosmeticIngredient Dictionary and Handbook (INCI), 12th Edition, 2008, hereinincorporated by reference. Such examples include, but are not limitedto, the following: block polymers, e.g., Poloxamer 124; ethoxylatedalcohols e.g., Ceteth-2, Ceteareth-20, Laureth-3; ethoxylated fattyesters and oils, e.g., PEG-40 Hydrogenated Castor Oil, PEG-36 CastorOil, PEG-150 Distearate; glycerol esters, e.g., Polyglyceryl-3Diisostearate, Glyceryl Stearate; glycol esters, PEG-12 Dioleate,LEXEMUL P; phosphate esters, e.g., Cetyl Phosphate; polymericsurfactants, e.g., PVM/MA Copolymer, Acrylates/C10-30 Alkyl AcrylateCrosspolymer; quaternary surfactants, e.g., Cetrimonium Chloride;Silicone Based Surfactants, e.g., PEG/PPG-20/6 Dimethicone; SorbitanDerivatives, e.g., Sorbitan Stearate, Polysorbate 80; sucrose andglucose esters and derivatives, e.g., PEG-20 Methyl GlucoseSesquistearate; and sulfates of alcohols, e.g., Sodium Lauryl Sulfate.More generally, surfactants can be classified by their ionic type suchas anionic, cationic, nonionic, or amphoteric. They can also beclassified by their chemical structures, such as block polymers,ethoxylated alcohols, ethoxylated fatty esters and oils, glycerolesters, glycol esters, phosphate esters, polymeric surfactants,quaternary surfactants, silicone-based surfactants, sorbitanderivatives, sucrose and glucose esters and derivatives, and sulfates ofalcohols.

F. Manufacture

The compositions of the invention may be manufactured by methods andequipment known in the art for manufacture of pharmaceutical productsincluding topical, injectable, and oral liquid products. Such methodsinclude, but are not limited to the use of mechanical mixers,dissolvers, dispersers, homogenizers, and mills. Non-limiting examplesinclude LIGHTNIN propeller mixers, COWLES dissolvers, IKA ULTRA TURRAXdispersers, SILVERSON homogenizers, LEE counter-rotating side-scrapingmixers, in-line and in-tank rotor-stator homogenizers, 3-roll mills,ointment mills, and rotor-stator mills. “All-in-one” vacuum mixingsystems that have a rotating side-scraping mixer plus an in-tankhomogenizer may also be used. Such mixers include, but are not limitedto OLSA mixers, FRYMA-KORUMA mixers, and LEE TRI-MIX TURBO-SHEARkettles. The compositions of the invention can be manufactured fromsmall laboratory scale batches using laboratory mixing equipment tofull-scale production batches.

II. Enhanced Topical Delivery Methods

In one aspect of the invention, there is disclosed a method forenhancing penetration of taxane nanoparticles into a skin malignancy,including a skin cancer and/or a cutaneous metastasis, the methodcomprising applying to the affected area of the skin malignancy thetopical compositions disclosed herein. In a preferred embodiment, themethod comprises applying to the affected area of the skin malignancy ahydrophobic composition which comprises a hydrophobic carrier, one ormore volatile silicone fluids, and a plurality of taxane nanoparticles.In some embodiments, the taxane nanoparticles are paclitaxelnanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles. Insome embodiments, the taxane nanoparticles, including paclitaxelnanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles,have a mean particle size (number) of from 0.01 microns to 1.5 microns,or from 0.01 microns to 1.2 microns, or from 0.01 microns to 1 micron,or from 0.01 microns to less than 1 micron, or from 0.01 microns to 0.9microns, or from 0.01 microns to 0.8 microns, or from 0.01 microns to0.7 microns, or from 0.1 microns to 1.5 microns, or from 0.1 microns to1.2 microns, or from 0.1 microns to 1 micron, or from 0.1 microns toless than 1 micron, or from 0.1 microns to 0.9 microns, or from 0.1microns to 0.8 microns, or from 0.1 to 0.7 microns, or from 0.2 micronsto 1.5 microns, or from 0.2 microns to 1.2 microns, or from 0.2 micronsto 1 micron, or from 0.2 microns to less than 1 micron, or from 0.2microns to 0.9 microns, or from 0.2 microns to 0.8 microns, or from 0.2microns to 0.7 microns, or from 0.3 microns to 1.5 microns, or from 0.3microns to 1.2 microns, or from 0.3 microns to 1 micron, or from 0.3microns to less than 1 micron, or from 0.3 microns to 0.9 microns, orfrom 0.3 microns to 0.8 microns, or from 0.3 microns to 0.7 microns, orfrom 0.4 microns to 1.5 microns, or from 0.4 microns to 1.2 microns, orfrom 0.4 microns to 1 micron, or from 0.4 microns to less than 1 micron,or from 0.4 microns to 0.9 microns, or from 0.4 microns to 0.8 microns,or from 0.4 microns to 0.7 microns, or from 0.5 microns to 1.5 microns,or from 0.5 microns to 1.2 microns, or from 0.5 microns to 1 micron, orfrom 0.5 microns to less than 1 micron, or from 0.5 microns to 0.9microns, or from 0.5 microns to 0.8 microns, or form 0.5 microns to 0.7microns, or from 0.6 microns to 1.5 microns, or from 0.6 microns to 1.2microns, or from 0.6 microns to 1 micron, or from 0.6 microns to lessthan 1 micron, or from 0.6 microns to 0.9 microns, or from 0.6 micronsto 0.8 microns, or from 0.6 microns to 0.7 microns. In otherembodiments, the taxane nanoparticles are paclitaxel nanoparticles. Insome embodiments, the paclitaxel nanoparticles have an SSA of at least18, at least 19, at least 20, at least 21, at least 22, at least 23, atleast 24, at least 25, at least 26, at least 27, at least 28, at least29, at least 30, at least 31, at least 32, at least 33, at least 34, orat least 35 m²/g. In other embodiments, the paclitaxel nanoparticleshave an SSA of 18 m²/g to 50 m²/g, or 20 m²/g to 50 m²/g, or 22 m²/g to50 m²/g, or 25 m²/g to 50 m²/g, or 30 m²/g to 50 m²/g, or 18 m²/g to 45m²/g, or 20 m²/g to 45 m²/g, or 22 m²/g to 45 m²/g, or 25 m²/g to 45m²/g, or 30 m²/g to 45 m²/g, or 18 m²/g to 40 m²/g, or 20 m²/g to 40m²/g, or 22 m²/g to 40 m²/g, or 25 m²/g to 40 m²/g, or 30 m²/g to 40m²/g. In some embodiments, the paclitaxel nanoparticles have a bulkdensity (not-tapped) of 0.05 g/cm³ to 0.15 g/cm³, or 0.05 g/cm³ to 0.20g/cm³. In various embodiments, the hydrophobic carriers are non-polarand/or non-volatile. In some embodiments, the hydrophobic carrierscomprise a hydrocarbon. In other embodiments, the hydrophobic carrierscomprise petrolatum, mineral oil, and paraffin. In some embodiments, themineral oil is heavy mineral oil. In some embodiments, the concentrationof the volatile silicone fluid in the composition formulation is at anamount effective to enhance skin penetration of the taxane nanoparticlesas compared to the formulation without the volatile silicone fluid. Asuitable method for measuring penetration into a skin malignancy can beby use of an in vitro Franz diffusion cell (FDC) system using humancadaver skin. A suitable in vitro Franz diffusion cell system isdescribed in Example 9 below. In some embodiments, the one or morevolatile silicone fluid is at a concentration from 5 to 24% w/w. Inother embodiments, the concentration of the one or more volatilesilicone fluid is from 5 to 20% w/w. In other embodiments, the one ormore volatile silicone fluid is at a concentration of from 5 to 18% w/w.In still other embodiments, the concentration of the one or morevolatile silicone fluid is 13% w/w. In various embodiments, theconcentration of the one or more volatile silicone fluid can be 5, 5.5,6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5,14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5,21, 21.5, 22, 22.5, 23, 23.5, or 24% w/w or any percentage derivabletherein of the total composition weight. In various embodiments, the oneor more volatile silicone fluid is cyclomethicone. In other embodiments,the cyclomethicone is cyclopentasiloxane. In some embodiments, thehydrophobic compositions do not contain additional penetrationenhancers. In other embodiments, the hydrophobic compositions do notcontain additional volatile solvents. In still other embodiments, thehydrophobic compositions do not contain a surfactant. In otherembodiments, the hydrophobic compositions are free of/do not include orcontain alcohols, or C₁ to C₄ aliphatic alcohols, or C₁ to C₅ aliphaticalcohols. In various embodiments, the taxane can be paclitaxel,docetaxel, or cabazitaxel. In some embodiments, the skin malignancy is askin cancer and/or a cutaneous metastasis. In some embodiments, thehydrophobic compositions are anhydrous. In other embodiments, thehydrophobic compositions are sterile. In other embodiments, thehydrophobic compositions are non-sterile. In other embodiments, thehydrophobic compositions have a low bioburden. In some embodiments, thehydrophobic compositions are semi-solid compositions. In still otherembodiments, the hydrophobic compositions are ointments. In someembodiments, the hydrophobic compositions are semi-solid compositions,including ointments, and have a viscosity of from 12,500 cps to 247,500cps, or from 25,000 cps to 150,000 cps as measured at room temperatureby a Brookfield RV viscometer using a small sample adapter with a SC4-14spindle and a 6R chamber at 5 rpm with an equilibration time of 2minutes. An alternative method for performing viscosity measurements ofthe hydrophobic, semi-solid compositions is using a Brookfield RVviscometer on a helipath stand with the helipath on, with a T-E spindleat 10 RPM at room temperature for 45 seconds. In some embodiments, thehydrophobic compositions are semi-solid compositions, includingointments, and have a viscosity of from 25,000 cps to 500,000 cps, orfrom 25,000 cps to 400,000 cps, or from 25,000 cps to 350,000 cps, orfrom 25,000 cps to 300,000 cps, or from 50,000 cps to 500,000 cps, orfrom 50,000 cps to 400,000 cps, or from 50,000 cps to 350,000 cps, orfrom 50,000 cps to 300,000 cps, or from 75,000 cps to 500,000 cps, orfrom 75,000 cps to 400,000 cps, or from 75,000 cps to 350,000 cps, orfrom 75,000 cps to 300,000 cps, or from 100,000 cps to 500,000 cps, orfrom 100,000 cps to 400,000 cps, or from 100,000 cps to 350,000 cps, orfrom 100,000 cps to 300,000 cps using a Brookfield RV viscometer on ahelipath stand with the helipath on, with a T-E spindle at 10 RPM atroom temperature for 45 seconds. In some embodiments, the hydrophobiccompositions are not sprays and are not sprayable.

In another aspect of the inventions, disclosed is a method of enhancingpenetration of taxane nanoparticles into a skin malignancy comprisingtopically applying a hydrophobic composition comprising a plurality oftaxane nanoparticles to the surface of the skin malignancy, wherein thepenetration of the taxane nanoparticles from the hydrophobic compositionis greater than the penetration of taxane nanoparticles from asuspension of taxane nanoparticles in an aqueous based composition. Asuitable method for determining penetration of taxane nanoparticles in askin malignancy is by an in vitro Franz diffusion cell (FDC) systemusing human cadaver skin. A suitable in vitro Franz diffusion cellsystem is described in Example 9 below. In some embodiments, the taxanenanoparticles have a mean particle size (number) from 0.1 microns to 1.5microns. In other embodiments, the taxane nanoparticles are paclitaxelnanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles. Inother embodiments, the hydrophobic composition further comprises ahydrophobic carrier. In other embodiments, the skin malignancy is a skincancer or a cutaneous metastasis.

III. Methods for the Inhibition of Crystal Growth in Formulations

In one aspect of the invention, disclosed are methods of inhibiting thegrowth of crystalline taxane nanoparticles, the method comprisingcontacting the taxane nanoparticles with a hydrophobic carrier. In someembodiments, the taxane nanoparticles are paclitaxel nanoparticles,docetaxel nanoparticles, or cabazitaxel nanoparticles. In someembodiments, the taxane nanoparticles are paclitaxel nanoparticles. Inother embodiments the composition is anhydrous. In other embodiments,the hydrophobic carriers comprise a hydrocarbon. In other embodiments,the hydrocarbon is petrolatum, mineral oil, or paraffin wax, or mixturesthereof. In some embodiments, the mineral oil is heavy mineral oil. Insome embodiments, the compositions further comprises one or morevolatile silicone fluids. In other embodiments, the volatile siliconefluid is cyclomethicone. In other embodiments, the cyclomethicone iscyclopentasiloxane.

In another aspect of the invention, disclosed are methods of inhibitingthe growth of a dispersion of crystalline taxane nanoparticles in anaqueous based carrier, the method comprising adding poloxamer 407, aquaternary ammonium compound, or a cross-linked acrylic acid polymer tothe aqueous based carrier at the time of manufacture. In someembodiments, the additive is poloxamer 407. In various embodiments, thequaternary ammonium compound is the additive and is benzalkoniumchloride or benzethonium chloride. In some embodiments, the quaternaryammonium compound is benzalkonium chloride. In some embodiments, thecross-linked acrylic acid polymer is the additive and is Carbomer. Insome embodiments, the taxane nanoparticles are paclitaxel nanoparticles,docetaxel nanoparticles, or cabazitaxel nanoparticles.

IV. Topical Treatment of Skin Malignancies

The methods of the invention include methods of treatment of skinmalignancies including skin cancers and cutaneous metastases in apatient by topically applying to the affected area (topical therapy)compositions disclosed herein comprising taxanes. The “affected area” ofa skin malignancy can include at least a portion of the skin where theskin malignancy lesion (tumor) is visibly present on the outermostsurface of the skin or directly underneath the surface of the skin(epithelial/dermal covering), and can include areas of the skin in theproximity of the skin malignancy likely to contain visibly undetectablepreclinical lesions. In some embodiments, the taxane is paclitaxel. Inother embodiments, the taxane is docetaxel or cabazitaxel. In someaspects, the compositions are hydrophobic and can comprise a hydrophobiccarrier. In other aspects, the compositions are aqueous basedcompositions and can comprise an aqueous carrier. In some embodiments,the carrier is anhydrous. In some embodiments, the taxanes are aplurality of taxane nanoparticles. In some embodiments, the plurality oftaxane nanoparticles are suspended within the compositions. In otheraspects, the taxanes are solubilized in the compositions.

A preferred method for the topical treatment of a skin malignancycomprises topically administering to the affected area a hydrophobiccomposition comprising a continuous hydrophobic carrier, one or morevolatile silicone fluids, and a plurality of taxane nanoparticles,wherein the taxane nanoparticles are suspended within the composition,wherein the mean particle size (number) of the taxane nanoparticles isfrom 0.1 microns to 1.5 microns or from 0.01 microns to 1.5 microns, andwherein the concentration of the taxane nanoparticles is at an amounteffective to provide a therapeutic improvement in the condition of theskin malignancy. In some embodiments, the taxane nanoparticles arepaclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxelnanoparticles. In some embodiments, the taxane nanoparticles, includingpaclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxelnanoparticles have a mean particle size (number) of from 0.01 microns to1.5 microns, or from 0.01 microns to 1.2 microns, or from 0.01 micronsto 1 micron, or from 0.01 microns to less than 1 micron, or from 0.01microns to 0.9 microns, or from 0.01 microns to 0.8 microns, or from0.01 microns to 0.7 microns, or from 0.1 microns to 1.5 microns, or from0.1 microns to 1.2 microns, or from 0.1 microns to 1 micron, or from 0.1microns to less than 1 micron, or from 0.1 microns to 0.9 microns, orfrom 0.1 microns to 0.8 microns, or from 0.1 to 0.7 microns, or from 0.2microns to 1.5 microns, or from 0.2 microns to 1.2 microns, or from 0.2microns to 1 micron, or from 0.2 microns to less than 1 micron, or from0.2 microns to 0.9 microns, or from 0.2 microns to 0.8 microns, or from0.2 microns to 0.7 microns, or from 0.3 microns to 1.5 microns, or from0.3 microns to 1.2 microns, or from 0.3 microns to 1 micron, or from 0.3microns to less than 1 micron, or from 0.3 microns to 0.9 microns, orfrom 0.3 microns to 0.8 microns, or from 0.3 microns to 0.7 microns, orfrom 0.4 microns to 1.5 microns, or from 0.4 microns to 1.2 microns, orfrom 0.4 microns to 1 micron, or from 0.4 microns to less than 1 micron,or from 0.4 microns to 0.9 microns, or from 0.4 microns to 0.8 microns,or from 0.4 microns to 0.7 microns, or from 0.5 microns to 1.5 microns,or from 0.5 microns to 1.2 microns, or from 0.5 microns to 1 micron, orfrom 0.5 microns to less than 1 micron, or from 0.5 microns to 0.9microns, or from 0.5 microns to 0.8 microns, or form 0.5 microns to 0.7microns, or from 0.6 microns to 1.5 microns, or from 0.6 microns to 1.2microns, or from 0.6 microns to 1 micron, or from 0.6 microns to lessthan 1 micron, or from 0.6 microns to 0.9 microns, or from 0.6 micronsto 0.8 microns, or from 0.6 microns to 0.7 microns. In otherembodiments, the taxane nanoparticles are paclitaxel nanoparticles. Insome embodiments, the paclitaxel nanoparticles have an SSA of at least18, at least 19, at least 20, at least 21, at least 22, at least 23, atleast 24, at least 25, at least 26, at least 27, at least 28, at least29, at least 30, at least 31, at least 32, at least 33, at least 34, orat least 35 m²/g. In other embodiments, the paclitaxel nanoparticleshave an SSA of 18 m²/g to 50 m²/g, or 20 m²/g to 50 m²/g, or 22 m²/g to50 m²/g, or 25 m²/g to 50 m²/g, or 30 m²/g to 50 m²/g, or 18 m²/g to 45m²/g, or 20 m²/g to 45 m²/g, or 22 m²/g to 45 m²/g, or 25 m²/g to 45m²/g, or 30 m²/g to 45 m²/g, or 18 m²/g to 40 m²/g, or 20 m²/g to 40m²/g, or 22 m²/g to 40 m²/g, or 25 m²/g to 40 m²/g, or 30 m²/g to 40m²/g. In some embodiments, the paclitaxel nanoparticles have a bulkdensity (not-tapped) of 0.05 g/cm³ to 0.15 g/cm³, or 0.05 g/cm³ to 0.20g/cm³. In various embodiments, the hydrophobic carriers are non-polarand/or non-volatile. In some embodiments, the hydrophobic carrierscomprise a hydrocarbon. In other embodiments, the hydrophobic carrierscomprise petrolatum, mineral oil, and paraffin. In some embodiments, themineral oil is heavy mineral oil. In some embodiments, the volatilesilicone fluid is at a concentration of from 5 to 24% w/w. In otherembodiments, the volatile silicone fluid is at a concentration of from 5to 20% w/w. In other embodiments, the volatile silicone fluid is at aconcentration of from 5 to 18% w/w. In other embodiments, theconcentration of the volatile silicone fluid is 13% w/w. In someembodiments, the volatile silicone fluid is cyclomethicone. In otherembodiments, the cyclomethicone is cyclopentasiloxane. In variousembodiments, the hydrophobic compositions are free of/do not include orcontain additional penetration enhancers. In some embodiments, thehydrophobic compositions are free of/do not include or containlaurocapram, and/or diethylene glycol monoethyl ether (DGME), and/orisopropyl myristate, and/or alpha tocopherol. In other embodiments, thehydrophobic compositions are free of/do not include or containadditional volatile solvents. In other embodiments, the hydrophobiccompositions are free of/do not include or contain a surfactant. Inother embodiments, the hydrophobic compositions are free of/do notinclude or contain alcohols, C₁-C₄ aliphatic alcohols, or C₁ to C₅aliphatic alcohols. In some embodiments, the hydrophobic compositionscomprise one or more volatile silicone fluids, but do not containadditional silicone materials. In some embodiments, the hydrophobiccompositions are free of/do not include hyaluronic acid; and/or are freeof/do not include a conjugate of hyaluronic acid and a taxane; and/orare free of/do not include a conjugate of hyaluronic acid andpaclitaxel; and/or are free of/do not include a polymer or abiodegradable polymer; and/or are free of/do not include a poloxamer,styrene-isobutylene-styrene (SIBS), a polyanhydride copolymer,polycaprolactone, polyethylene glycol, Poly(bis(P-carboxyphenoxy)propane-sebacic acid, and/or poly(D, Llactic-co-glycolic acid) (PLGA).

The concentration of the taxane nanoparticles is at an amount effectiveto provide a therapeutic improvement in the condition of the skinmalignancy. This improvement can be indicated by visual observation andmeasurement of the affected area after treatment to include at least oneof the following accomplishments: (a) a reduction of the size of theskin malignancy lesions (tumors); (b) a reduction of the number of theskin malignancy lesions (tumors); (c) elimination of the skin malignancylesions (tumors); and (d) a reduction of pain at the site of the skinmalignancy lesions (tumors). The concentration of the taxanenanoparticles can be from 0.05 to 10% w/w, or the concentration of thetaxane nanoparticles can be from 0.05 to 5% w/w, or the concentration ofthe taxane nanoparticles can be from 0.1 to 5% w/w, or the concentrationof the taxane nanoparticles can be 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4,0.5, 0.6, 0.7, 0.75, 0.8, 0.9, 1.0, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6,1.7, 1.75, 1.8, 1.9, 2.0, 2.1, 2.2, 2.25, 2.3, 2.4, 2.5, 2.6, 2.7, 2.75,2.8, 2.9, 3.0, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9,4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6, 4.7, 4.75, 4.8, 4.9, 5, 6, 7,8, 9, or 10% w/w or any percentage derivable therein of the totalcomposition weight. In some embodiments, the taxane nanoparticles arepaclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxelnanoparticles. In other embodiments, the taxane nanoparticles arepaclitaxel nanoparticles. In some embodiments, the paclitaxelnanoparticles are at a concentration of about 0.05 to less than 3% w/w,or about 0.05 to about 2% w/w, or about 0.05 to about 1% w/w, or about0.05 to about 0.3% w/w, or about 0.05 to about 0.2% w/w, or about 0.05to about 0.15% w/w, or about 0.1 to about 2% w/w, or about 0.1 to about1% w/w, or about 0.1 to about 0.3% w/w, or about 0.1 to about 0.2% w/w,or about 0.15 to about 2% w/w, or about 0.15 to about 1% w/w, or about0.15 to about 0.3% w/w, or about 0.3 to about 2% w/w, or about 0.3 toabout 1% w/w, or about 1 to about 2% w/w, or about 0.2 to about 0.4%w/w, or about 0.5 to about 1.5% w/w, or about 1.5 to about 2.5% w/w inthe compositions. In other embodiments, the concentration of thepaclitaxel nanoparticles is 80 to 120% of 1% w/w (i.e., 0.8 to 1.2%w/w), or 80 to 120% of 0.05% w/w, or 80 to 120% of 0.1% w/w, or 80 to120% of 0.15% w/w, or 80 to 120% of 0.2% w/w, or 80 to 120% of 0.25%w/w, or 80 to 120% of 0.3% w/w, or 80 to 120% of 0.35% w/w, or 80 to120% of 0.4% w/w, or 80 to 120% of 0.45% w/w, or 80 to 120% of 0.5% w/w,or 80 to 120% of 0.55% w/w, or 80 to 120% of 0.6% w/w, or 80 to 120% of0.65% w/w, or 80 to 120% of 0.7% w/w, or 80 to 120% of 0.75% w/w, or 80to 120% of 0.8% w/w, or 80 to 120% of 0.85% w/w, or 80 to 120% of 0.9%w/w, or 80 to 120% of 0.95% w/w, or 80 to 120% of 1.5% w/w, or 80 to120% of 2% w/w, or 80 to 120% of 2.5% w/w.

In some embodiments, the hydrophobic compositions are sterile. In otherembodiments, the hydrophobic compositions are non-sterile. In otherembodiments, the hydrophobic compositions have a low bioburden. In otherembodiments, the hydrophobic compositions are anhydrous. In someembodiments, the hydrophobic compositions are semi-solid compositions.In still other embodiments, the hydrophobic compositions are ointments.In some embodiments, the hydrophobic compositions are semi-solidcompositions, including ointments, and have a viscosity of from 12,500cps to 247,500 cps, or from 25,000 cps to 150,000 cps as measured atroom temperature by a Brookfield RV viscometer using a small sampleadapter with a SC4-14 spindle and a 6R chamber at 5 rpm with anequilibration time of 2 minutes. An alternative method for performingviscosity measurements of the hydrophobic, semi-solid compositions isusing a Brookfield RV viscometer on a helipath stand with the helipathon, with a T-E spindle at 10 RPM at room temperature for 45 seconds. Insome embodiments, the hydrophobic compositions are semi-solidcompositions, including ointments, and have a viscosity of from 25,000cps to 500,000 cps, or from 25,000 cps to 400,000 cps, or from 25,000cps to 350,000 cps, or from 25,000 cps to 300,000 cps, or from 50,000cps to 500,000 cps, or from 50,000 cps to 400,000 cps, or from 50,000cps to 350,000 cps, or from 50,000 cps to 300,000 cps, or from 75,000cps to 500,000 cps, or from 75,000 cps to 400,000 cps, or from 75,000cps to 350,000 cps, or from 75,000 cps to 300,000 cps, or from 100,000cps to 500,000 cps, or from 100,000 cps to 400,000 cps, or from 100,000cps to 350,000 cps, or from 100,000 cps to 300,000 cps using aBrookfield RV viscometer on a helipath stand with the helipath on, witha T-E spindle at 10 RPM at room temperature for 45 seconds. In someembodiments, the hydrophobic compositions are not sprays and are notsprayable. In some embodiments, the compositions are not dry powders. Insome embodiments, the compositions do not solely include the taxanenanoparticles.

In some embodiments, the skin malignancy is a skin cancer. The method ofthe invention can be used to treat a variety of skin cancers including,but not limited to melanoma, basal cell carcinoma, squamous cellcarcinoma, and Kaposi's sarcoma (including AIDS related Kaposi'ssarcoma). In other embodiments the skin malignancy is a cutaneousmetastasis. The methods of the invention can be used to treat cutaneousmetastases derived from a variety of primary cancers. The cutaneousmetastasis can be from, but not limited to, one or more of the of thefollowing primary malignancies: breast, lung, nasal, sinus, larynx, oralcavity, colon (large intestine), rectum, stomach, ovary, testis,bladder, prostate, cervical, vaginal, thyroid, endometrial, kidney,esophagus, pancreas, liver, melanoma, and Kaposi's sarcoma. In someembodiments, the cutaneous metastasis is from lung cancer, breastcancer, colon cancer, oral cancer, ovarian cancer, kidney cancer,esophageal cancer, stomach cancer, or liver cancer. In some embodiments,the cutaneous metastasis is from breast cancer. In some embodiments, thecutaneous metastasis is a non-melanoma cutaneous metastasis.

The amount of the hydrophobic composition topically applied to theaffected area of the skin malignancy can vary depending on the size ofthe affected area and the concentration of the paclitaxel in thecomposition, but generally can be applied at approximately the thicknessof a dime to fully cover the affected area. Another suitable method fordetermining the amount of composition to apply is the “Finger-Tip Unit”(FTU) approach. One FTU is the amount of topical composition that issqueezed out from a standard tube along an adult's fingertip (Thisassumes the tube has a standard 5 mm nozzle). A fingertip is from thevery end of the finger to the first crease in the finger. Thecomposition can be applied with a gloved hand or spatula or other meansof topical administration. In some embodiments, the composition isapplied to skin malignancies which have an intact skin covering(epithelial/dermal covering). In some embodiments, the composition isapplied to ulcerated areas where the skin malignancy lesion is on thesurface of the skin or where the skin covering is degraded and the skinmalignancy lesion is exposed. In some embodiments, the composition isnot applied to ulcerated areas. The affected area can be gently cleansedwith water (and mild soap if required) and dried prior to application.Once the composition is applied, the application site can be coveredwith an occlusive dressing such as TEGADERM® or SOLOSITE®. The dosing ofthe composition can vary, but generally can include an application once,twice, or three times daily at approximately the same time each dayuntil the condition is improved or eliminated. The therapeuticimprovement of the condition of the skin malignancy as a result of themethods of treatment disclosed herein can be indicated by visualobservation and measurement of the affected area after treatment toinclude at least one of the following accomplishments: (a) a reductionof the size of the skin malignancy lesions (tumors); (b) a reduction ofthe number of the skin malignancy lesions (tumors); (c) elimination ofthe skin malignancy lesions (tumors); and (d) a reduction of pain at thesite of the skin malignancy lesions (tumors).

EXAMPLES

The present invention will be described in greater detail by way ofspecific examples. The following examples are offered for illustrativepurposes only, and are not intended to limit the invention in anymanner. Those of skill in the art will readily recognize a variety ofnoncritical parameters, which can be changed or modified to yieldessentially the same results.

Example 1—Solubility of Paclitaxel in Various Solvents

The solubility of paclitaxel was determined in various solvents by thefollowing method: (a) for each solvent, about 2 g of the solvent wasweighed into a clear glass vial, (b) approximately 0.1 g of paclitaxelwas added to each vial, (c) each vial was mixed with a stir bar on amagnetic stirrer for 2 hours at room temperature, (d) each vial was thenchecked every 1-2 hours to see if the solution became clear. If yes, anadditional approximately 0.1 g of paclitaxel was added to the vial andmixing was continued. Step “d” was continued for each vial for a totalof 48 hours.

The solution from each vial was measured for paclitaxel concentrationusing an HPLC method based on Agilent Technical Application Note forPaclitaxel “Analysis of Taxol by HPLC”, 2002, and modified to use a 227nm detection wavelength, rather than 204 nm (the 227 nm wavelength isused in the USP paclitaxel monograph, and reduces the solvent effectsseen at lower wavelengths).

The solubility values are shown in Table 1.

TABLE 1 Paclitaxel Solubility Solvent at RT Hexylene Glycol 4.07% w/wDiethylene Glycol Monoethyl 33.10% w/w Ether, NF (TRANSCUTOL P)Propylene Carbonate 4.74% w/w Super Refined Oleic Acid, NF 0.041% w/wSuper Refined Oleyl Alcohol, NF 0.38% w/w Diisopropyl Adipate (CERAPHYL230) 3.51% w/w Medium Chain Triglycerides, NF 0.32% w/w PropyleneGlycol, USP 0.88% w/w Polyethylene Glycol 400, NF 22.30% w/w BenzylAlcohol, NF 17.02% w/w Isopropyl Myristate, NF 0.048% w/w Mineral Oil,USP (heavy) 0.3 ppm Dimethyl Isosorbide 38.22% w/w Purified Water, USP<0.05 ppm

Example 2 Observations of Paclitaxel Nanoparticle Crystals in VariousSubstances and Solutions of Substances

Paclitaxel nanoparticles were dispersed in various substances andaqueous solutions of substances and observed for crystal growth. Theresults are shown in Table 2.

TABLE 2 Visual observation by light microscopy- Substance ConcentrationNeedle shaped crystals observed? Aqueous Based Carriers Purified Water100% Yes, >5 μm, @ 5 days, RT & 60 C. Polysorbate 80 0.5% in water Yes,<5 μm @ 22 days, RT & 60 C. PEG 400 10% in water Yes, >5 μm @ 22 days,RT & 60 C. Benzalkonium chloride (50%) 2% in water No, <5 μm @ 7 days &21 days, RT Magnesium nitrate 5% in water Yes, >5 μm @ 3 days, RTMannitol 5% in water Yes, >5 μm, @ 7 days, RT Sorbitol 5% in waterYes, >5 μm, @ 7 days, RT Povidone 1% in water Yes, <5 μm @ 7 days & 21days, RT Lecithin 1% in water Yes, >10 μm, @ 24 hrs, RT Sodium laurylsulfate 2% in water Yes, >5 μm, @ 7 days, RT Ammonium lauryl sulfate 2%in water Yes, >5 μm @ 3 days, RT Aluminum sulfate 0.1-0.2% in waterYes, >5 μm, @ 7 days, RT Sodium phosphate monobasic 0.75% in waterYes, >5 μm, @ 7 days, RT Zinc acetate 1.2% in water Yes, >5 μm, @ 7days, RT Proline 3% in water Yes, >5 μm, @ 7 days, RT Hydroxyethylcellulose 1% in water Yes, >5 μm, @ 7 days, RT CARBOPOL ULTREZ 10 0.5%in water No, <5 μm, @ 8 days & 21 days, RT (with Ammonium hydroxide asneutralizer) Hydroxypropyl methylcellulose 1% in water Yes, >5 μm @ 3days, RT Saline 0.9% NaCl in water Yes, >10 μm, @ 7 days , RT & 60 C.Polysorbate 80 0.5% in Saline Yes, >5 μm @ 7 days, RT & 60 C. Poloxamer407 2% in water No, <5 μm @ 5 & 7 days, RT Poloxamer 188 2% in waterYes, >5 μm @ 7 days, RT Polyoxyl 40 Hydrogenated Castor 1% in water Yes,<5 μm @ 6 days, RT Oil (KOLLIPHOR RH40) Vitamin E TPGS 0.5% in waterYes, <5 μm @ 6 days, RT Hydrophobic Carriers Mineral Oil USP (heavy)100% No, <5 μm @ 3 days, RT & 40 C. Light Mineral Oil NF 100% No, <5 μm@ 3 days, RT & 40 C. FOMBLIN HC04 100% No, <5 μm @ 4, 7 & 13 days, RTST-Cyclomethicone 5 NF 100% No, <5 μm @ 24 hrs & 13 days, RTDimethicone, 1000 cSt 100% No, <5 μm @ 24 hrs & 6 days, RT Castor Oil100% No, <5 μm @ 24 hrs & 9 days, RT

The paclitaxel nanoparticles crystals did not grow in any of thehydrophobic carriers. Also, the nanoparticles did not grow in aqueoussolutions of benzalkonium chloride, CARBOPOL ULTREZ 10, or poloxamer407.

Example 3 Particle Size, SSA, and Bulk Density Analysis of PaclitaxelNanoparticles

The particle size of the paclitaxel nanoparticles lots used in theformulas listed in Table 3 and Tables 16-19 were analyzed by thefollowing particle size method using an ACCUSIZER 780:

Instrument Parameters:

Max. Concentration: 9000 particles/mL, No. containers: 1, Sensor Range:Summation, Lower Detection Limit: 0.5 μm, Flow Rate: 30 mL/min, No.Analysis pulls: 4, Time between pulls: 1 sec, Pull volume: 10 mL, TareVolume: 1 mL, Prime volume: 1 mL, Include First Pull: Not Selected.

Sample Preparation:

Placed a scoop of paclitaxel nanoparticle API into a clean 20 mL vialand added approximately 3 mL of a filtered (0.22 μm) 0.1% w/w solutionof SDS to wet the API, then filled the remainder of the vial with theSDS solution. Vortexed for 5-10 minutes and sonicated in a water batchfor 1 minute.

Method:

Filled a plastic bottle with filtered (0.22 μm) 0.1% w/w SDS solutionand analyzed the Background. Pipetted a small amount of the paclitaxelnanoparticles sample suspension, <100 μL, into the bottle of 0.1% w/wSDS solution while stirring; placed the ACCUSIZER inlet tube into thebottle and ran sample through instrument. As necessary, added more SDSsolution or paclitaxel sample suspension to reach a desired runconcentration of 6000-8000 particle count.

Particles Size Results (Based on Number-Weighted DifferentialDistribution):

Paclitaxel nanoparticles lot used in formulas listed in Table 3: Mean:0.861 μm, Mode: 0.572 μm, Median: 0.710 μm. Paclitaxel nanoparticles lotused in formulas listed in Tables 16-19: Mean: 0.83 μm.

The specific surface area (SSA) of the paclitaxel nanoparticles lotsused in the formulas listed in Table 3 and Tables 16-19 were analyzed bythe Brunauer-Emmett-Teller (“BET”) isotherm method described above. Thepaclitaxel nanoparticles lot used in the formulas listed in Table 3 hadan SSA of 41.24 m²/g. The paclitaxel nanoparticles lot used in theformulas listed in Tables 16-19 had an SSA of 26.72 m²/g.

The bulk density (not-tapped) of the paclitaxel nanoparticles lot usedin the formulas listed in Table 3 was 0.05 g/cm³. The bulk density(not-tapped) of the paclitaxel nanoparticles lot used in the formulaslisted in Tables 16-19 was 0.09 g/cm³.

Example 4 Anhydrous Hydrophobic Compositions of Paclitaxel Nanoparticleswith Hydrophobic Carriers

Anhydrous hydrophobic compositions of paclitaxel nanoparticles withhydrophobic carriers are listed in Table 3.

TABLE 3 Formula Number Component (% w/w) F4 F5 F6 F7 F8 F9 F10 F11 F12F13 A B C Paclitaxel 1.0 1.0 1.0 1.0 0.5 2.0 1.0 1.0 1.0 1.0 0.5 0.5 0.5Nanoparticles FOMBLIN HC04 — — — 15.0  — — — — — — — — — Mineral Oil USP10.0  — 5.0 — 5.0 5.0 — — — — — — — ST-Cyclomethicone — 5.0 13.0  —13.0  13.0  13.0  13.0  18.0  15.0  qs ad qs ad qs ad 5 NF(Dow Corning)100 100 100 Oleyl Alcohol — 5.0 — — — — — 1.0 — — — — 5.0 IsopropylMyristate NF — 5.0 — — — — 5.0 1.0 — 3.0 — 35   5.0 Dimethicone — — — —— — — — — — 5.0 5.0 5.0 Fumed Silica — — — — — — — — — — 5.5 5.5 2.8Cetostearyl Alcohol NF — — — — — — — — 0.5 — — — — Paraffin Wax NF 5.05.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 — — — White Petrolatum qs ad qs adqs ad qs ad qs ad qs ad qs ad qs ad qs ad qs ad — — — USP (Spectrum) 100100 100 100 100 100 100 100 100 100

Procedure for F4-F13: Prepared a slurry of the paclitaxel nanoparticleswith a portion of the cyclomethicone (or mineral oil (F4) or FOMBLIN(F7)). Heated the petrolatum to 52±3° C. and added the remainingingredients and mixed until melted and homogeneous. Added the paclitaxelslurry and mixed until homogenous. Mixed and allowed the batch to coolto 35° C. or below. An ointment was formed.

Example 5 Physical and Chemical Stability of Anhydrous Compositions ofPaclitaxel Nanoparticles with Hydrophobic Carriers

The anhydrous hydrophobic composition samples were stored at 25° C. and30° C. in 20 mL glass scintillation vials. The assay of paclitaxel wasconducted using HPLC. The results of the assay and appearance stabilitystudies are shown in Table 4 and Table 5 below. The viscosity wasmeasured at room temperature with a Brookfield RV viscometer using asmall sample adapter with a SC4-14 spindle and a 6R chamber at 5 rpmwith an equilibration time of 2 minutes. The viscosity results are shownin Table 6 below.

TABLE 4 Stability at 25° C. Assay (% of target) Appearance Formula T = 01 month 2 month 3 month T = 0 1 month 2 month 3 month F4 95.3 99.6 100.399.5 Off-white Off-white to Off-white to Off-white to ointment yellowointment yellow ointment yellow ointment F5 98.2 101.7 101.0 100.9Off-white Off-white to Off-white to Off-white to ointment yellowointment yellow ointment yellow ointment F6 97.2 100.5 97.9 98.4Off-white Off-white to Off-white to Off-white to ointment yellowointment yellow ointment yellow ointment F6** 98.0 98.5 100.2 NPOff-white to Off-white to Off-white to NP yellow ointment yellowointment yellow ointment F8 107.6 100.5 101.1 NP Off-white to Off-whiteto Off-white to NP yellow ointment yellow ointment yellow ointment F995.6 98.3 101.2 NP Off-white to Off-white to Off-white to NP yellowointment yellow ointment yellow ointment F10 98.6 103.8 101.2 NPOff-white to Off-white to Off-white to NP yellow ointment yellowointment yellow ointment F11 99.8 99.8 100.9 NP Off-white to Off-whiteto Off-white to NP yellow ointment yellow ointment yellow ointment F1298.7 98.3 99.1 NP Off-white to Off-white to Off-white to NP yellowointment yellow ointment yellow ointment F13 96.5 93.9 96.0 NP Off-whiteto Off-white to Off-white to NP yellow ointment yellow ointment yellowointment **repeat batch

TABLE 5 Stability at 30° C. Assay (% of target) Appearance Formula T = 01 month 2 month 3 month T = 0 1 month 2 month 3 month F4 95.3 99.5 100.199.7 Off-white Off-white to Off-white to Off-white to ointment yellowointment yellow ointment yellow ointment F5 98.2 103.2 101.3 99.2Off-white Off-white to Off-white to Off-white to ointment yellowointment yellow ointment yellow ointment F6 97.2 102.1 98.0 95.0Off-white Off-white to Off-white to Off-white to ointment yellowointment yellow ointment yellow ointment F6** 98.0 98.7 102.0 NPOff-white to Off-white to Off-white to NP yellow ointment yellowointment yellow ointment F8 107.6 99.9 103.0 NP Off-white to Off-whiteto Off-white to NP yellow ointment yellow ointment yellow ointment F995.6 101.4 101.9 NP Off-white to Off-white to Off-white to NP yellowointment yellow ointment yellow ointment F10 98.6 100.9 102.9 NPOff-white to Off-white to Off-white to NP yellow ointment yellowointment yellow ointment F11 99.8 99.8 99.1 NP Off-white to Off-white toOff-white to NP yellow ointment yellow ointment yellow ointment F12 98.799.8 99.5 NP Off-white to Off-white to Off-white to NP yellow ointmentyellow ointment yellow ointment F13 96.5 95.6 96.5 NP Off-white toOff-white to Off-white to NP yellow ointment yellow ointment yellowointment **repeat batch

TABLE 6 Viscosity Stability Viscosity (cps) F4 F5 F6 F7 T = 0 87,50044,300 49,500 81,800 1 month @ 25° C. 90,300 68,800 57,000 NP 3 month @25° C. 101,000 47,800 38,000 NP 1 month @ 30° C. 123,300 49,300 50,800NP 2 month @ 30° C. 112,300 53,500 38,000 NP 3 month @ 30° C. 121,30060,500 54,000 NP

Example 6 Particle Size Analysis of Paclitaxel Nanoparticles inAnhydrous Compositions with Hydrophobic Carriers

Particle Size Method Using an ACCUSIZER Model 770/770A.

Instrument Parameters:

Sensor: LE 0.5 μm-400 μm, Sensor Range: Summation, Lower DetectionLimit: 0.5 μm, Collection time: 60 sec, Number Channels: 128, VesselFluid Vol: 100 mL, Flow Rate: 60 mL/min, Max Coincidence: 8000particles/mL, Sample Vessel: Accusizer Vessel, Sample Calculation: None,Voltage Detector: greater than 10 V, Particle Concentration Calculation:No, Concentration Range: 5000 to 8000 particles/mL, Automatic DataSaving: Selected, Subtract Background: Yes, Number of Autocycles: 1.

Sample Preparation:

Added an aliquot of the sample formulation into a scintillation vial.Using a spatula, smeared the sample along the inner walls of the vial.Added about 20 mL of 2% Lecithin in ISOPAR-G™ (C10-11 isoparaffin)solution to the vial. Sonicated the vial for 1 minute. Insured that thesample had adequately dispersed in the solution.

Method:

Filled the sample vessel with a filtered (0.22 μm) 2% Lecithin inISOPAR-G solution and analyzed the background. Using a pipette,transferred a portion of the prepared sample to the vessel whilestirring. Diluted or added sample to the vessel as necessary to providea coincidence level between 5000 to 8000 particles/mL. Initiated theanalysis through the instrument and verified that the coincidence levelwas 5000 to 8000 particles/mL for the analysis.

The results of the particle size analysis are shown in Table 7 and Table8 below.

TABLE 7 Particle size stability at 25° C. Mean particle size, μm(number) Formula Initial 1 month 3 month 6 month 12 month F4 0.77 0.71NP NP NP F5 0.72 0.71 NP NP NP F6 0.72 0.71 NP 0.71 0.72 F6** 0.70 NP0.70 NP NP F8 0.71 NP 0.71 NP NP F9 0.70 NP 0.70 NP NP F10 0.69 NP 0.69NP NP F11 0.69 NP 0.69 NP NP F12 0.70 NP 0.70 NP NP F13 0.69 NP 0.70 NPNP A 0.72 NP NP NP NP B 0.77 NP NP NP NP C 0.84 NP NP NP NP **repeatbatch

TABLE 8 Particle size stability at 30° C. Mean particle size, μm(number) Formula Initial 1 month 3 month 6 month 12 month F4 0.77 0.73NP NP NP F5 0.72 0.70 NP NP NP F6 0.72 0.70 NP 0.70 0.73 F6** 0.70 NP0.72 NP NP F8 0.71 NP 0.71 NP NP F9 0.70 NP 0.71 NP NP F10 0.69 NP 0.69NP NP F11 0.69 NP 0.70 NP NP F12 0.70 NP 0.71 NP NP F13 0.69 NP 0.71 NPNP **repeat batch

As can be seen by the data, the particle size of paclitaxelnanoparticles in samples F4 through F6 did not grow larger than 20% ofthe initial mean particle size when stored at room temperature (25° C.)and at 30° C. for 1 month. The particle size of paclitaxel nanoparticlesin sample F6 did not grow larger than 20% of the initial mean particlesize when stored at room temperature (25° C.) and at 30° C. for 6 monthsand for 12 months. The particle size of paclitaxel nanoparticles insamples F6**(repeat batch with the same formula as F6) and F8 throughF13 did not grow larger than 20% of the initial mean particle size whenstored at room temperature (25° C.) and at 30° C. for 3 months.

Example 7 Aqueous Based Compositions of Paclitaxel Nanoparticles

Aqueous based compositions of paclitaxel nanoparticles are shown inTable 9.

TABLE 9 Formula Number Component (% w/w) F1 F2 F3 D E F G H PaclitaxelNanoparticles 1.0 1.0 1.0 0.5 0.5 0.5 0.5 0.5 DGME (TRANSCUTOL P) 5.05.0 — 5.0 5.0 5.0 5.0 5.0 PEG 400 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0Glycerin 10.0 10.0 10.0  5.0 5.0 5.0 5.0 5.0 Polysorbate 80 1.0 1.0 1.00.1 0.1 0.1 0.1 0.1 Poloxamer 407 2.0 2.0 2.0 — — — — — Povidone K900.15 0.15  0.15 0.1 0.1 0.1 0.1 0.1 Benzyl Alcohol 0.5 0.5 0.5 — — — — —Methylparaben 0.15 0.15  0.15  0.15  0.15  0.15  0.15  0.15Propylparaben 0.02 0.02  0.02  0.02  0.02  0.02  0.02  0.02 BenzalkoniumChloride (50%) — 1.0 1.0 — — 0.1 0.1 — CARBOPOL 974 P — — —  0.75 — — —— CARBOPOL ULTREZ 10 0.5 — — — 0.5 — — — Trolamine Solution (10%) qs pH— — qs pH qs pH — — — 5.5 5.5 5.5 Hydroxypropyl Methylcellulose — 1.01.0 — — 2.0 — — (K200M Pharm) Purified Water qs ad qs ad qs ad qs ad qsad qs ad qs ad qs ad 100 100 100 100 100 100 100 100

Samples were observed for crystal growth of the paclitaxelnanoparticles. The results are shown in Table 10 below.

TABLE 10 Formula Visual observation by light microscopy - Number Needleshaped crystals observed? D No, <5 μm @ 24 hrs & 6 days, RT E No, <5 μm@ 24 hrs & 6 days, RT F No, <5 μm @ 24 hrs & 6 days, RT G No, <5 μm @ 24hrs & 6 days, RT H Yes, >5 μm @ 24 hrs & 6 days, RT

As can be seen by the data, the presence of benzalkonium chloride,CARBOPOL 974P, or CARBOPOL ULTREZ 10 inhibited the growth of crystals inthe aqueous based compositions.

Example 8 Particle Size Analysis of Paclitaxel Nanoparticles in AqueousBased Compositions

Particle Size Method Using an ACCUSIZER Model 770/770A.

Instrument Parameters:

Sensor: LE 0.5 μm-400 μm, Sensor Range: Summation, Lower DetectionLimit: 0.5 μm, Collection time: 60 sec, Number Channels: 128, VesselFluid Vol: 100 mL, Flow Rate: 60 mL/min, Max Coincidence: 8000particles/mL, Sample Vessel: Accusizer Vessel, Sample Calculation: None,Voltage Detector: greater than 10 V, Particle Concentration Calculation:No, Concentration Range: 5000 to 8000 particles/mL, Automatic DataSaving: Selected, Subtract Background: Yes, Number of Autocycles: 1.

Sample Preparation:

Added an aliquot of the sample formulation into a scintillation vial.Using a spatula, smeared the sample along the inner walls of the vial.Added about 20 mL of 0.2 μm filtered distilled water to the vial.Sonicated the vial for 1 minute. Insured that the sample had adequatelydispersed in the solution.

Method:

Filled the sample vessel with 0.2 μm filtered distilled water andanalyzed the background. Using a pipette, transferred a portion of theprepared sample to the vessel while stirring. Diluted or added sample tothe vessel as necessary to provide a coincidence level between 5000 to8000 particles/mL. Initiated the analysis through the instrument andverified that the coincidence level was 5000 to 8000 particles/mL forthe analysis.

The results of the particle size analysis are shown in Table 11 below.

TABLE 11 Particle size of aqueous based compositions Mean particle size,μm (number) Formula Initial 6 month at RT F1 1.06 0.82 F2 0.74 0.77 F30.70 0.77 D 0.80 NP E 0.79 NP F 0.85 NP

As can be seen by the data of formulas F1, F2, and F3 in Table 11, thepresence of benzalkonium chloride, CARBOPOL 974P, or CARBOPOL ULTREZ 10inhibited the growth of crystals in the aqueous based compositions suchthat the mean particle size of the drug nanoparticles did not growlarger than 20% of the initial mean particle size when the compositionwas stored at room temperature for 6 months.

Example 9 In Vitro Skin Penetration Diffusion Study

A study to determine the rate and extent of in vitro skin permeation ofthe formulas F1 through F13 into and through intact human cadaver skinusing a Franz diffusion cell system was conducted. Concentrations ofpaclitaxel were measured in the receptor chamber of the diffusion cellat varying time points. Upon conclusion of the diffusion study, the skinwas tape stripped and split into epidermal and dermal layers. Thepaclitaxel in the epidermal and dermal tissue was extracted using anextraction solvent and also analyzed.

Analytical Method:

A Mass spectrometry (MS) method was developed for analyzing thepaclitaxel. The MS conditions were as follows in Table 12 below.

TABLE 12 Instrument: Agilent 1956B MS (TM-EQ-011) Column: XBridge C184.6 × 100 mm, 5 μm Mobile Phase: A: Acetonitrile B: 0.1% Formic acid inwater Gradient: Time (minutes) % B 0 50%  2 5% 5 5% Flow Rate: 1 mL/minColumn Temperature: 30° C. MS Detection: SIM 854.4 + Frag 180, Gain 20Injection Volume: 20 μL Retention time: ~2.86 minFranz Diffusion Cell (FDC) Study—Methodology

Skin Preparation:

Intact human cadaver skin was purchased from New York FirefightersTissue Bank (NFFTB). The skin was collected from the upper back anddermatomed by the tissue bank to a thickness of ˜500 μm. Upon receipt ofthe skin from the tissue bank, the skin was stored frozen at −20° C.until the morning of the experiment. Prior to use, the skin was removedfrom the freezer and allowed to fully thaw at room temperature. The skinwas then briefly soaked in a PBS bath to remove any residualcryoprotectants and preservatives. Only areas of the skin that werevisually intact were used during the experiment. For each study, twoseparate donors were used, each donor having a corresponding threereplicates.

Receptor Fluid Preparation:

Based on the results of preliminary solubility data, a receptor fluid of96 wt % phosphate buffered saline (“PBS”) at pH 7.4 and 4 wt % hydroxylpropyl beta cyclodextrin (HPBCD) was chosen. The solubility of theactive in the receptor fluid (˜0.4 μg/mL) was shown to be adequate tomaintain sink conditions during the studies. The receptor fluid wasdegassed by filtering the receptor fluid through a ZapCap CR 0.2 μmmembrane while pulling vacuum. The filtered receptor fluid was stirredfor an additional 20 minutes while maintaining vacuum to ensure completedegassing.

Diffusion Cell Assembly:

The cadaver skin was removed from the freezer and allowed to defrost ina bio-safety hood for 30 minutes. The skin was thoroughly defrostedprior to opening the package. The cadaver skin was removed from thepackage and placed on the bio-safety hood countertop with the stratumcorneum side up. The skin was patted dry with a Kim Wipe, then sprayedwith fresh PBS and patted dry again. This process was repeated 3 moretimes to remove any residues present on the skin. The receptor wellswere then filled with the degassed receptor fluid. A Teflon coated stirbar was added to each receptor well. The defrosted cadaver skin wasexamined and only areas with even thickness and no visible damage to thesurface were used. The skin was cut into ˜2 cm×2 cm squares. The skinpiece was centered on the donor wells, stratum corneum (SC) side up. Theskin was centered and the edges flattened out. The donor and receptorwells were then aligned and clamped together with a clamp. Additionalreceptor fluid was added where necessary. Any air bubbles present wereremoved by tilting the cell, allowing air to escape along the sampleport. Diffusion cells were then placed in to the stirring dry blockheaters and allowed to rehydrate for 20 minutes from the receptor fluid.The block heaters were maintained at 32° C. throughout the experimentwith continuous stirring. The skin was allowed to hydrate for 20 minutesand the barrier integrity of each skin section was tested. Once themembrane integrity check study was complete, the entire receptor chambervolume was replaced with the receptor fluid.

Formulation Application Procedure:

The formulations were applied to the stratum corneum of the skin. Aone-time dosing regimen was used for this study. The test articles wereapplied as 10 μl doses to the skin using a positive displacementNichiryo pipetter. The formulations were then spread across the surfaceof the skin using a glass rod. Cells were left uncapped during theexperiment. The theoretical dose of paclitaxel per cell is shown inTable 13 below.

TABLE 13 Nominal Theoretical Formula % w/w Paclitaxel formulationPaclitaxel Number in formula dose per cell dose per cell F1 1.0 wt % 10μl 182 μg/cm² F2 1.0 wt % 10 μl 182 μg/cm² F3 1.0 wt % 10 μl 182 μg/cm²F4 1.0 wt % 10 μl 182 μg/cm² F5 1.0 wt % 10 μl 182 μg/cm² F6 1.0 wt % 10μl 182 μg/cm² F7 1.0 wt % 10 μl 182 μg/cm² F6* 1.0 wt % 10 μl 182 μg/cm²F8 0.5 wt % 10 μl  91 μg/cm² F9 2.0 wt % 10 μl 364 μg/cm² F10 1.0 wt %10 μl 182 μg/cm² F11 1.0 wt % 10 μl 182 μg/cm² F12 1.0 wt % 10 μl 182μg/cm² F13 1.0 wt % 10 μl 182 μg/cm² *repeat analysis

Sampling of Receptor Fluid:

At 3, 6, 12 and 24 hours, 300 μL sample aliquots were drawn from thereceptor wells using a graduated Hamilton type injector syringe. Freshreceptor medium was added to replace the 300 μL sample aliquot.

Tape Stripping and Heat Splitting:

At 24 hours, the skin was wiped clean using PBS/ethanol soaked KimWipes.After the residual formulation was wiped off and the skin dried withKimWipes, the stratum corneum was tape stripped three times—each tapestripping consisting of applying cellophane tape to the skin withuniform pressure and peeling the tape off. The tape strips werecollected and frozen for future analysis. The first three tape stripsremove the uppermost layer of the stratum corneum and act as an extraskin cleaning step. The active is typically not considered fullyabsorbed in this area. These tape strips are usually only analyzed for amass balance assay. After the skin was tape stripped, the epidermis ofeach piece was then separated from the underlying dermal tissue usingtweezers or a spatula. The epidermis and dermal tissue were collectedand placed in 4 mL borosilicate glass vials. After all the skin pieceswere separated, an aliquot of the extraction solvent was added to theglass vial. This process consisted of adding 2 mL of DMSO to the vialand incubating for 24 hours at 32° C. After the extraction time wasover, 300 μL sample aliquots of the extraction fluid were collected andfiltered.

Analysis of Samples:

Sample aliquots were analyzed for paclitaxel using the analytical methodas described above.

Results:

The results in Table 14 below show the delivered dose of paclitaxel(μg/cm²) in the receptor fluid at various time points (transdermal flux)and the concentration of paclitaxel (μg/cm²) delivered into theepidermis and dermis (penetration) after 24 hours elapsed time forformulations F1 through F13. FIG. 1 graphically shows the concentrationof paclitaxel (μg/cm²) delivered into the epidermis for formulas F1through F7. FIG. 2 graphically shows the concentration of paclitaxel(μg/cm²) delivered into the epidermis for formulas F6*(repeat analysis)and F8 through F13. FIG. 3 graphically shows the concentration ofpaclitaxel (μg/cm2) delivered into the dermis for formulas F1 throughF7. FIG. 4 graphically shows the concentration of paclitaxel (μg/cm2)delivered into the dermis for formulas F6*(repeat analysis) and F8through F13.

Note: Formulas F1 through F6 were tested in one in vitro study, andformulas F6* and F8 through F13 were tested in a second separate invitro study, with different cadaver skin lots. Analysis of formula F6was repeated in the second study (and notated as F6*) so that it couldbe evaluated and compared with the other formulas in the second study.

TABLE 14 Paclitaxel Delivered Dose (μg/cm²) Receptor Fluid ReceptorFluid Receptor Fluid Receptor Fluid Formula 3 hrs 6 hrs 12 hrs 24 hrsEpidermis Dermis F1 0.000 0.000 0.000 0.000 0.202 0.030 F2 0.000 0.0000.000 0.000 0.161 0.042 F3 0.000 0.000 0.000 0.000 0.056 0.138 F4 0.0000.000 0.000 0.000 0.690 0.639 F5 0.000 0.000 0.000 0.004 0.780 1.337 F60.000 0.000 0.000 0.000 1.927 2.088 F7 0.000 0.000 0.000 0.000 0.6330.882 F6* 0.000 0.000 0.000 0.000 4.910 1.508 F8 0.000 0.000 0.000 0.0003.155 1.296 F9 0.000 0.000 0.000 0.000 7.010 5.679 F10 0.000 0.000 0.0000.000 5.470 0.494 F11 0.000 0.000 0.000 0.000 3.262 1.098 F12 0.0000.000 0.000 0.000 5.269 1.571 F13 0.000 0.000 0.000 0.000 4.903 0.548*repeat analysis

As can be seen by the results in Table 14, the transdermal flux of thepaclitaxel through the skin (epidermis and dermis) was none or only anegligible amount, i.e., less than 0.01 μg/cm². As can be seen by theresults in Table 14 and FIGS. 1, 2, 3 & 4, the penetration of paclitaxelinto the skin (epidermis and dermis) was far greater with the anhydroushydrophobic formulations (F4 through F13) than with the aqueousformulations (F1 through F3), even though the aqueous formulationscontained the skin penetration enhancer DGME (TRANSCUTOL P). The resultsalso show that the anhydrous hydrophobic formulations withcyclomethicone exhibited greater skin penetration (epidermis and dermis)over the anhydrous hydrophobic formulations without cyclomethicone.Additionally, the results show that the addition of other skinpenetration enhancers to the anhydrous hydrophobic formulationscontaining cyclomethicone had little or no effect on the skinpenetration (epidermis and dermis) of these compositions.

Example 10—Formulations for Cutaneous Metastasis Studies

The following ointment formulations shown in Table 15 were prepared foruse in cutaneous metastasis studies.

TABLE 15 Formula No. F14 F15 F16 F17 Component (% w/w) (0.15%) (0.3%)(1%) (2%) Paclitaxel Nanoparticles 0.15 0.3 1.0 2.0 Mineral Oil USP 5.05.0 5.0 5.0 ST-Cyclomethicone 5 13.0 13.0 13.0 13.0 NF (Dow Corning)Paraffin Wax NF 5.0 5.0 5.0 5.0 White Petrolatum USP qs ad qs ad qs adqs ad (Spectrum) 100 100 100 100

The formulas listed in Table 15 containing paclitaxel nanoparticles weremanufactured each in a 6 kg batch size. The formulas were then packagedin 15 gm laminate tubes.

The manufacturing processes for lots F14, F15, and F16 were as follows:The petrolatum, mineral oil, paraffin wax, and a portion of thecyclomethicone were added to a vessel and heated to 52±3° C. whilemixing with a propeller mixer until melted and homogeneous. Thepaclitaxel nanoparticles were added to a vessel containing anotherportion of cyclomethicone and first mixed with a spatula to wet thenanoparticles, then mixed with an IKA Ultra Turrax Homogenizer with aS25-25G dispersing tool until a homogeneous slurry is obtained whilekeeping the container in an ice/water bath. The slurry was then added tothe petrolatum/paraffin wax container while mixing with the propellermixer followed by rinsing with the remaining portion of cyclomethiconeand mixed until the batch was visually homogeneous while at 52±3° C. Thebatch was then homogenized using a Silverson homogenizer. Afterward, thebatch was mixed with a propeller mixer until a homogeneous ointment wasformed and the batch cooled to 35° C. or below.

The manufacturing process for lot F17 was as follows: The petrolatum andparaffin wax were added to a vessel and heated to 52±3° C. while mixingwith a propeller mixer until melted and homogeneous. The paclitaxelnanoparticles were added to a vessel containing the cyclomethicone and aportion of mineral oil, and first mixed with a spatula to wet thenanoparticles, then mixed with an IKA Ultra Turrax Homogenizer with aS25-25G dispersing tool until a homogeneous slurry is obtained whilekeeping the container in an ice/water batch. The slurry was then addedto the petrolatum/paraffin wax container while mixing with the propellermixer followed by rinsing with the remaining portion of mineral oil andmixed until the batch was visually homogeneous while at 52±3° C. Thebatch was then homogenized using a Silverson homogenizer. Afterward, thebatch was mixed with a propeller mixer until a homogeneous ointment wasformed and the batch cooled to 35° C. or below.

The chemical and physical analytical results for each formula in Table15 are shown in Tables 16-19 for T=0, 1 month, and 3 months at 25° C.

TABLE 16 Formula No. F14 (0.15%) Test T = 0 1 month 3 month Appearance(note1) conforms conforms conforms Assay, % target 103.4 103.2 101.1Viscosity (note 2) 131000 cps 147000 cps 159500 cps Mean Particle Size(number) 0.71 μm 0.70 μm 0.70 μm (note1) Off-white to yellow ointment(note 2) Brookfield RV viscometer on a helipath stand with the helipathon, with a T-E spindle at 10 RPM at room temperature for 45 seconds.

TABLE 17 Formula No. F15 (0.3%) Test T = 0 1 month 3 month Appearance(note1) conforms conforms conforms Assay, % target 101.2 101.9 102.5Viscosity (note 2) 195500 cps 154000 cps 153500 cps Mean Particle Size(number) 0.72 μm 0.71 μm 0.70 μm (note1) Off-white to yellow ointment(note 2) Brookfield RV viscometer on a helipath stand with the helipathon, with a T-E spindle at 10 RPM at room temperature for 45 seconds.

TABLE 18 Formula No. F16 (1%) Test T = 0 1 month 3 month Appearance(note1) conforms conforms conforms Assay, % target 102.1 102.2 102.7Viscosity (note 2) 205000 cps 218000 cps 180000 cps Mean Particle Size(number) 0.70 μm 0.70 μm 0.70 μm (note1) Off-white to yellow ointment(note 2) Brookfield RV viscometer on a helipath stand with the helipathon, with a T-E spindle at 10 RPM at room temperature for 45 seconds.

TABLE 19 Formula No. F17 (2%) Test T = 0 1 month 3 month Appearance(note1) conforms conforms conforms Assay, % target 101.7 101.1 105.0Viscosity (note 2) 158000 cps 177000 cps 162000 cps Mean Particle Size(number) 0.70 μm 0.69 μm 0.69 μm (note1) Off-white to yellow ointment(note 2) Brookfield RV viscometer on a helipath stand with the helipathon, with a T-E spindle at 10 RPM at room temperature for 45 seconds.

Example 11—Individual Patient Expanded Access Trial for TopicalTreatment of Cutaneous Metastatic Breast Cancer

The formulations in Table 15 are to be used in an individual humanpatient expanded access trial for topical treatment of cutaneousmetastatic breast cancer. In this expanded access trial, a subject withcutaneous metastasis from breast cancer will receive topical applicationof 0.3% paclitaxel nanoparticles ointment (formula F15 from Table 15) tothe affected area. Prior to study entry, historical information will becollected from the subject including surgical history, radiationhistory, chemotherapy, and time-to-ulceration for other cutaneousmetastases. Photographs (with a ruler) and measurements of metastasis(treatment area) will be taken in the clinic prior to initiation oftreatment. No biopsies or blood work will be done. Prior to application,the treatment area will be gently cleansed with water (and mild soap ifrequired) and dried. The subject will apply the ointment with a glovedhand over metastases which have skin covering (epithelial/dermalcovering). The ointment will not be applied on ulcerated areas. A layerof ointment the “thickness of a dime” will be applied on metastasis asdirected by clinical medical staff at the first treatment. The ointmentapplication site will be covered with an occlusive dressing (TEGADERM orSOLOSITE). The subject will re-treat the metastasis once daily atapproximately the same time for two weeks using the same technique asthe initial application. The subject will then return to the clinic forreview of response and any adverse events will be recorded in the clinicrecord. A photograph will be taken of the treated site (with a ruler)and the lesion will be measured. The subject can be treated for anothertwo weeks with physician approval, and the subject will return to theclinic for a final visit where photographs of the treatment site (with aruler) will be taken and the lesion will be measured. Adverse eventswill be recorded in clinic records. If requested by the subject and thephysician, a higher or lower dose following the above plan may beauthorized after a review of data and discussion with the physician. Nowash out period will be required. If requested by the subject and thephysician, further treatment with the same dose (0.3% paclitaxelnanoparticles ointment), a dose escalation (1.0% and/or 2.0% paclitaxelnanoparticles ointment), or a dose deescalation (0.15% paclitaxelnanoparticles ointment) may be authorized after a review of data, anddiscussion with the physician. If erythema, cracking or ulcerationdevelop, the subject will wash the treatment site with water (and mildsoap if required) and return to the clinic for evaluation. A photograph(with a ruler) will be taken of the treatment site, the lesion will bemeasured, and no further ointment will be applied unless approved by thephysician. The endpoint of the trial will show a reduction of thecutaneous metastasis demonstrating a therapeutic improvement of thecutaneous metastatic condition.

Example 12—Phase 1/2 Dose-Rising, Safety, Tolerability and EfficacyStudy for Cutaneous Metastases

Three of the formulations in Table 15 above were used in a FDA approvedPhase 1/2 dose-rising, safety, tolerability and efficacy study forcutaneous metastases in humans. The study is currently on-going. Thiswas a Phase 1/2, open-label, dose-rising study evaluating the safetytolerability, and preliminary efficacy of three of the formulations fromTable 15: F14 (0.15%), F16 (1.0%), and F17 (2.0%) applied topicallytwice daily for 28 days to non-melanoma cutaneous metastases.

A treatment area of 50 cm² on the trunk or extremities containing atleast one eligible lesion was determined at baseline by the RECIST(version 1.1) definition of measurable tumors (greater than or equal to10 mm in its longest diameter). All lesions within the treatment areawere measured by caliper to confirm eligibility. Using a gloved hand,subjects applied one fingertip unit (FTU) of the formulation to the 50cm² treatment area twice daily at approximately the same time each dayfor 28 days. A FTU is defined as the amount of ointment formulationexpressed from a tube with a 5-mm diameter nozzle, applied from thedistal skin-crease to the tip of the index finger of an adult. Subjectsattended the clinic on Day 1 for dose application training andobservation of the first treatment application. Additional visits wereon Days 8, 15, 29, and 43. The final visit was completed 30 days afterthe last study drug dose to review adverse events. Study participationis separated into a dose-escalation phase and a dose expansion phase.

Dose Escalation Phase: During the dose-escalation phase the studyfollowed a standard 3+3 dose-ascending design, with the first cohort ofthree subjects commencing treatment with formulation F14 (0.15%). Asafety monitoring committee reviewed all available data after the lastsubject in each cohort of three subjects completed 15 days of treatmentto determine whether dose escalation may continue.

Dose Expansion Phase: In the dose-expansion phase, additional subjectswere enrolled to reach a maximum of 12 total subjects at the dose leveldetermined in the dose escalation phase. Subjects in the dose expansionphase attended the clinic on the same visit days and received the sameevaluations as the dose escalation phase above.

Objectives: The primary objective of the study was to determine thepreliminary safety and tolerability of the formulations. The secondaryobjectives were to determine the preliminary efficacy of theformulations, to study potential reduction in pain in the treatmentarea, and to describe the pharmacokinetics of the formulations appliedto metastatic lesions.

Population: A minimum of two up to a maximum of 24 male and female humansubjects, greater than or equal to 18 years of age, with non-melanomacutaneous metastases.

Primary Endpoint: Safety and tolerability, as demonstrated by adverseevents, changes in laboratory assessments, physical examinationfindings, and vital signs.

Secondary Endpoints: For the purposes of the following secondaryendpoint for efficacy, eligible lesions were determined at baseline bythe RECIST (Version 1.1) definition of measurable tumors (greater thanor equal to 10 mm in its longest diameter (EISENHAUER et al. Newresponse evaluation criteria in solid tumors: revised RECIST guideline(version 1.1). European Journal of Cancer. 2009; 45; 228-247).

Objective Tumor Response, defined as the difference in the sum ofeligible tumor diameter(s) within the treatment area between baselineand Day 43 (i.e., 14 days after the last dose in the dose escalation andexpansion phases depending on dose regimen). Tumor surface area andresponse were assessed at all visits. Change in surface area wasassessed using a calibrated grid measurement system (ImageJ freeware)provided by the National Institutes of Health (NIH). Lesions weremeasured and analyzed using ImageJ.

Objective Clinical Response is defined as subjects with CompleteClinical Response (CR)+Partial Response (PR), further defined as thepercentage of patients who achieve complete clinical response or partialresponse 14 days after the last treatment with the formulation, measuredas change in the sum of the longest diameter(s) of eligible targetlesion(s) within the treatment area 14 days after last treatment. Theresponse to treatment was evaluated as a function of post-treatmenttotal diameter divided by pre-treatment total diameter.

Best Overall Response is defined as the best response recorded from thestart of the study treatment until the end of treatment, i.e., Day 43.

Complete Clinical Response (CR) is defined as absence of any detectableresidual disease in eligible lesion(s) within the treatment area;Partial Response (PR) is at least a 30% decrease in the sum of thediameters of the eligible lesions(s) within the treatment area comparedto bassline; and Progressive Disease (PD) is at least a 20% increase inthe sum of diameters of eligible lesion(s) within the treatment area,taking as a reference the smallest sum on study. In addition, the summust also demonstrate an absolute increase of at least 5 mm.

Stable Disease (SD) is defined as the sum of eligible lesion diameter(s)between that defined as PR or PD.

The appearance of new non-target lesions during participation in thisstudy does not constitute progressive disease.

Pain at the treatment area will be measures by the Numeric Rating Scale(NRS-11). Change in pain will be analyzed from baseline to Day 43.

Systemic exposure as determined by: T_(max), C_(max), AUC.

Preliminary Results: Preliminary results for the on-going study includephotos of skin metastatic lesions on the chest of a woman with Stage 4breast cancer. FIG. 5 is a photo taken at baseline (Day 1) and shows theindex lesion (arrow) covered with congealed exudate from an ulceratedlesion. FIG. 6 is a photo taken at Day 8 after topical treatment of theformulation F14 (0.15%) applied over the same treatment site twice perday. The surface of the lesion contains an area of epidermal loss andpresumptive ulceration limited to the dermis. FIG. 7 is a photo at Day15 after topical treatment of the formulation F14 (0.15%) applied overthe same treatment site twice per day. A small amount of old exudate canbe seen on the medial portion of the lesion as well as no apparentepidermal ulceration. FIG. 8 is a photo at Day 29 after topicaltreatment of the formulation F14 (0.15%) applied over the same treatmentsite twice per day. The lesion appears to be epithelialized with noevidence of ulceration. In contrast, the natural history of anulcerative cutaneous breast cancer metastasis is rapid expansion andfurther penetration through the dermis once the epidermal surface isbreached by the tumor. Thus, the topical application of the treatmentformulations to cutaneous metastatic disease provides a benefit to thepatients.

Example 13—Dermal Toxicity Study

A dermal toxicity study was conducted using the formulations shown inTable 20.

TABLE 20 Formula No. F18 (0.0%) F19 F20 F21 Component (% w/w) Placebo(0.3%) (1%) (3%) Paclitaxel Nanoparticles 0.0 0.3 1.0 3.0 Mineral OilUSP 5.0 5.0 5.0 5.0 ST-Cyclomethicone 5 13.0 13.0 13.0 13.0 NF (DowCorning) Paraffin Wax NF 5.0 5.0 5.0 5.0 White Petrolatum USP qs ad qsad qs ad qs ad (Spectrum) 100 100 100 100

The GLP-compliant study was conducted in Gottingen minipigs tocharacterize the toxicity of the formulations applied topically to 10%body surface area daily for 28 days. The 4 formulations shown in Table20 were applied at the maximal feasible volume of 2 mL/kg, correlatingto dose concentrations of 0.0, 0.3, 1.0, and 3%, which translate to doselevels of 0, 4.9, 16.5, and 49.9 mg/kg/day respectively. Reversibilityof findings was also evaluated following a 2-week recovery period.Parameters evaluated included clinical observations, mortality andmoribundity checks, dermal scoring, body weight, food consumption, eyeexaminations, test site photographs, electrocardiology, clinicalpathology, bioanalysis and toxicokinetic evaluation, organ weights,macroscopic pathology and histopathology. There were noformulation-related effects on survival, clinical signs, dermalirritation, body weights, body weight gains, food consumption,ophthalmic findings, or cardiology parameters. Minimal dermal irritationwas observed in all groups during the dosing phase and was consideredvehicle or procedurally related as the frequency and severity of thefindings were comparable between the placebo controls and activeformulation-treated groups. Thus, the presence of the paclitaxelnanoparticles in the formulations had a negligible effect on dermalirritation.

The invention claimed is:
 1. A method of treating a skin malignancy in asubject in need of treatment, the method comprising topicallyadministering to an affected area of the subject a hydrophobiccomposition comprising a plurality of nanoparticles of non-solubilizedtaxane, a hydrophobic carrier, and 5% w/w to 24% w/w of one or morevolatile silicone fluids, wherein the plurality of nanoparticlespenetrate into the dermal or epidermal portions of the affected area ofthe subject, wherein the nanoparticles of non-solubilized taxane areuncoated (neat) individual particles of non-solubilized taxane, andwherein the non-solubilized taxane is not bound to or conjugated to anysubstance.
 2. The method of claim 1, wherein the nanoparticles ofnon-solubilized taxane are in crystalline form.
 3. The method of claim1, wherein the nanoparticles of non-solubilized taxane are in amorphousform.
 4. The method of claim 1, wherein the nanoparticles ofnon-solubilized taxane have a mean particle size (number) from 0.1microns to 1.5 microns.
 5. The method of claim 1, wherein the taxane ispaclitaxel.
 6. The method of claim 5, wherein the nanoparticles ofnon-solubilized taxane have a specific surface area (SSA) of 18 m²/g to40 m²/g.
 7. The method of claim 6, wherein the nanoparticles ofnon-solubilized taxane contain not less than 90% by weight ofpaclitaxel.
 8. The method of claim 1, wherein the composition comprises0.1% w/w to 5% w/w of the plurality of the nanoparticles ofnon-solubilized taxane.
 9. The method of claim 1, wherein thenanoparticles of non-solubilized taxane are suspended within thecomposition.
 10. The method of claim 1, wherein the composition isanhydrous.
 11. The method of claim 1, wherein the hydrophobic carrier isnon-volatile and non-polar.
 12. The method of claim 1, wherein thehydrophobic carrier comprises a hydrocarbon.
 13. The method of claim 12,wherein the hydrocarbon is petrolatum, mineral oil, or paraffin wax, ormixtures thereof.
 14. The method of claim 1, wherein the one or morevolatile silicone fluids is cyclomethicone.
 15. The method of claim 1,wherein the composition does not contain a C₁-C₄ aliphatic alcohol, asurfactant, a protein, and/or a hyaluronic acid-taxane conjugate. 16.The method of claim 1, wherein the skin malignancy is a skin cancer. 17.The method of claim 16, wherein the skin cancer is melanoma, basal cellcarcinoma, squamous cell carcinoma, or Kaposi's sarcoma.
 18. The methodof claim 1, wherein the skin malignancy is a cutaneous metastasis. 19.The method of claim 18, wherein the cutaneous metastasis is from lungcancer, breast cancer, colon cancer, oral cancer, ovarian cancer, kidneycancer, esophageal cancer, stomach cancer, liver cancer, or Kaposi'ssarcoma.
 20. A method of treating a skin malignancy in a subject in needof treatment, the method comprising topically administering to anaffected area of the subject an anhydrous hydrophobic compositioncomprising a suspension of 0.1% w/w to 5% w/w of a plurality ofnanoparticles of non-solubilized taxane, petrolatum, and 5% w/w to 24%w/w of cyclomethicone, wherein the nanoparticles of non-solubilizedtaxane are uncoated (neat) individual particles of non-solubilizedtaxane, wherein the non-solubilized taxane is not bound to or conjugatedto any substance, wherein the nanoparticles of non-solubilized taxanehave a mean particle size (number) from 0.1 microns to 1.5 microns, andwherein the skin malignancy is a cutaneous metastasis, and wherein theplurality of nanoparticles penetrate into the dermal or epidermalportions of the affected area of the subject.
 21. The method of claim20, wherein the composition further comprises mineral oil or paraffinwax, or mixtures thereof.
 22. The method of claim 21, wherein the taxaneis paclitaxel, and wherein the nanoparticles of non-solubilized taxanecontain not less than 90% by weight of paclitaxel.
 23. The method ofclaim 22, wherein the nanoparticles of non-solubilized taxane have aspecific surface area (SSA) of 18 m²/g to 40 m²/g.